3-aryl-5,6-disubstituted pyridazines

ABSTRACT

The present invention provides compounds of Formula (I) or (II) salt form or prodrug thereof, wherein variables are defined herein, that are modulators of metalloproteases such as matrix metalloproteases (MMPs) and ADAMs. The compounds or compositions described herein can be used to treat diseases associated with metalloprotease activity including, for example, arthritis, cancer, cardiovascular disorders, skin disorders, inflammation or allergic conditions.

FIELD OF THE INVENTION

This invention relates generally to 3-aryl-5,6-disubstituted pyridazinesthat that have useful pharmacological properties. The invention furtherrelates to the use of such compounds for treating a variety ofinflammatory and immune system disorders and as probes for thelocalization of C5a receptors.

BACKGROUND OF THE INVENTION

C5a, a 74 amino acid peptide, is generated in the complement cascade bythe cleavage of the complement protein C5 by the complement C5convertase enzyme. C5a has both anaphylatoxic (e.g., bronchoconstrictingand vascular spasmogenic) and chemotactic effects. Therefore, it isactive in engendering both the vascular and cellular phases ofinflammatory responses. Because it is a plasma protein and, therefore,generally almost instantly available at a site of an inciting stimulus,it is a key mediator in terms of initiating the complex series of eventsthat results in augmentation and amplification of an initialinflammatory stimulus. The anaphylatoxic and chemotactic effects of theC5a peptide are believed to be mediated through its interaction with C5areceptor (CD88 antigen), a 52 kD membrane bound G-protein coupledreceptor (GPCR). C5a is a potent chemoattractant for polymorphonuclearleukocytes, bringing neutrophils, basophils, eosinophils and monocytesto sites of inflammation and/or cellular injury. C5a is one of the mostpotent chemotactic agents known for a wide variety of inflammatory celltypes. C5a also “primes” or prepares neutrophils for variousantibacterial functions (e.g., phagocytosis). Additionally, C5astimulates the release of inflammatory mediators (e.g., histamines,TNF-α, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) and therelease of lysosomal enzymes and other cytotoxic components fromgranulocytes. Among its other actions, C5a also promotes the productionof activated oxygen radicals and the contraction of smooth muscle.

Considerable experimental evidence implicates increased levels of C5a ina number of autoimmune diseases and inflammatory and related disorders.Agents that block the binding of C5a to its receptor other agents,including inverse agonists, which modulate signal transductionassociated with C5a-receptor interactions, can inhibit the pathogenicevents, including chemotaxis, associated with anaphylatoxin activitycontributing to such inflammatory and autoimmune conditions. The presentinvention provides such agents, and has further related advantages.

SUMMARY OF THE INVENTION

In certain aspects, the present invention provides3-aryl-5,6-disubstituted pyridazine analogues of Formula I:

or a pharmaceutically acceptable salts thereof, wherein:

-   R₂ is selected from the group consisting of —NR₄R₅, —NR₅R₆,    —(CR_(A)R_(B))OR₄, — C(R_(A′))═CR_(A)R_(B), Q, and —CR_(A)R_(B)Q;-   R₁ is selected from hydrogen, halogen, cyano, amino, optionally    substituted alkyl, optionally substituted alkenyl, optionally    substituted alkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkenyl, optionally substituted haloalkyl,    optionally substituted haloalkoxy, optionally substituted alkoxy,    optionally substituted cycloalkoxy, optionally substituted    (cycloalkyl)alkoxy, or optionally substituted heterocycloalkyl;-   R₃ is selected from halogen, hydroxy, amino, cyano, optionally    substituted alkyl, optionally substituted haloalkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted cycloalkyl, optionally substituted alkoxy, optionally    substituted haloalkoxy, optionally substituted hydroxyalkyl,    optionally substituted alkoxyalkyl, optionally substituted mono- and    di-alkylamino, optionally substituted aminoalkyl,    -E-(CR_(C)R_(D))_(m)—Z, or -E-(CR_(C)R_(D))_(m)—XR_(A); or-   R₁ and R₃, taken in combination form an optionally substituted fused    carbocyclic ring;-   R₄ is:    -   (i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl,        (C₃-C₂cycloalkyl)C₀-C₄alkyl, mono- or        di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered        heterocycloalkyl)C₀-C₄alkyl, arylC₀-C₄alkyl, or        heteroarylC₀₋₄alkyl, each of which is substituted with from 0 to        4 substituents independently chosen from R_(x), C₂-C₄alkanoyl,        mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and        di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered        heterocycloalkyl)C₀-C₄alkyl and XR_(y); or    -   (ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅        are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring        members in each ring, wherein the heterocycle is substituted        with from 0 to 4 substituents independently chosen from R_(x),        oxo and W—Z;-   R₅ is:    -   (i) hydrogen;    -   (ii) C₃-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        (C₃-C₂-carbocycle)C₀-C₄alkyl, each of which is substituted with        from 0 to 3 substituents independently chosen from halogen,        hydroxy, amino, cyano, C₃-C₄alkyl, C₁-C₄alkoxy, methylamino,        dimethylamino, trifluoromethyl and trifluoromethoxy; or    -   (iii) joined to R₄ or to R₆ to form an optionally substituted        heterocycle;-   R₆ is:    -   (i) optionally substituted (C₄-C₁₀-carbocycle)C₀-C₄alkyl,        optionally substituted (benzoC₄-C₇-carbocycle)C₀-C₄alkyl,        optionally substituted (C₃-C₇heterocycle)C₀-C₄alkyl, and        optionally substituted (benzoC₃-C₂heterocycle)C₀-C₄alkyl, each        of which is substituted with from 0 to 3 substituents        independently chosen from halogen, hydroxy, amino, cyano, COOH,        CONH₂, SO₂NH₂, C₁-C₄alkoxy, methylamino, dimethylamino,        trifluoromethyl, trifluoromethoxy, optionally substituted        phenyl, optionally substituted phenoxy, and C₁₋₃alkylenedioxy;        or    -   (ii) joined to R₅ to form an optionally substituted heterocycle;-   Ar is optionally substituted ortho-substituted phenyl, optionally    substituted naphthyl, or optionally substituted heteroaryl, wherein    Ar is optionally substituted heteroaryl when R₂ is —NR₄R₅;-   R_(A), R_(A)′, and R_(B), which may be the same or different, are    independently selected at each occurrence from: (i) hydrogen,    hydroxy, and (ii) alkyl groups, cycloalkyl groups, and    (cycloalkyl)alkyl groups, each of which is optionally substituted    with one or more substituent(s) independently selected from oxo,    hydroxy, halogen, cyano, amino, C₁₋₆alkoxy, mono- or    di-(C₁₋₆alkyl)amino, —NHC(═O)(C₁₋₆alkyl),    —N(C₁₋₆alkyl)C(O)(C₁₋₆alkyl), —NHS(O)_(n)(C₁₋₆alkyl), —    S(O)_(n)(C₁₋₆alkyl), —S(O)_(n)NH(C₁₋₆alkyl),    —S(O)_(n)N(C₁₋₆alkyl)(C₁₋₆alkyl), and Z;-   E is a single covalent bond, oxygen, or NR_(A);-   X is independently selected at each occurrence from —CHR_(B)—, —O—,    —C(═O)—, —C(═O)O—, —S(O)_(n)—, — NR_(B)—, —C(═O)NR_(B)—,    —S(O)_(n)NR_(B)—, —NR_(B)C(═O)—, or —NR_(B)S(O)_(n)—;-   Y and Z are independently selected at each occurrence from 3- to    7-membered carbocyclic or heterocyclic groups which are saturated,    unsaturated, or aromatic, which are optionally substituted with one    or more substituents independently selected from halogen, oxo,    hydroxy, amino, cyano, C₁₋₄alkoxy, mono- or di(C₁₋₄alkyl)amino, and    —S(O)_(n)(alkyl);-   Q is an optionally substituted carbocyclic or optionally substituted    heterocyclic group which are saturated, unsaturated or aromatic and    comprises between 3 and 18 ring atoms arranged in 1, 2, or 3 rings    which are fused, spiro or coupled by a bond;-   m is independently selected at each occurrence from integers ranging    from 0 to 8; and-   n is an integer independently selected at each occurrence from 0, 1,    and 2.

Within certain other aspects, compounds provided herein are3-aryl-5,6-disubstituted pyridazine analogues of Formula II:

or a pharmaceutically acceptable salts thereof, wherein:

-   Ar is substituted phenyl, optionally substituted naphthyl, or    optionally substituted heteroaryl;-   A is OR₄, NR₄R₅, or CR₄(XR_(y))₂;-   R₁ is chosen from:-   (i) hydrogen, halogen, amino, or cyano; and-   (ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,    C₁-C₄haloalkyl, C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino,    (C₃-C₇cycloalkyl)C₀-C₄alkyl, (3- to 7-membered    heterocycloalkyl)C₀-C₄alkyl or —S(O_(n))C₁-C₄alkyl, each of which is    substituted with from 0 to 4 substituents independently chosen from    R_(x);-   R₃ is selected from halogen, hydroxy, amino, cyano, optionally    substituted alkyl, optionally substituted alkenyl, optionally    substituted alkynyl, optionally substituted cycloalkyl, optionally    substituted alkoxy, optionally substituted alkoxyalkyl, optionally    substituted hydroxyalkyl, optionally substituted mono- and    di-alkylamino, optionally substituted aminoalkyl, optionally    substituted cycloalkyloxy, optionally substituted aryl, optionally    substituted arylalkyl, optionally substituted aryloxy, optionally    substituted arylalkyloxy, optionally substituted heterocycle,    optionally substituted heterocycle-oxy, -E-(CR_(C)R_(D))_(m)—Z, or    -E-(CR_(C)R_(D))_(m)—XR_(A);-   R₁, and R₃, taken in combination form an optionally substituted    fused carbocyclic ring;-   R₄ is:    -   (i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or        di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered        heterocycloalkyl)C₀-C₄alkyl, arylC₀-C₄alkyl, or        heteroarylC₀₋₄alkyl, each of which is substituted with from 0 to        4 substituents independently chosen from R_(x), C₂-C₄alkanoyl,        mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and        di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered        heterocycloalkyl)C₀-C₄alkyl and XR_(y); or    -   (ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅        are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring        members in each ring, wherein the heterocycle is substituted        with from 0 to 4 substituents independently chosen from R_(x),        oxo and W—Z;-   R₅ is:    -   (i) hydrogen;    -   (ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        (C₃-C₇-carbocycle)C₀-C₄alkyl, each of which is substituted with        from 0 to 3 substituents independently chosen from halogen,        hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino,        dimethylamino, trifluoromethyl and trifluoromethoxy; or    -   (iii) joined to R₄ to form an optionally substituted        heterocycle;    -   R₂ and R₉ are independently selected from hydrogen, halogen,        hydroxy, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,        C₁-C₆alkylamino or C₃-C₇cycloalkyl C₀-C₄alkyl;-   E is a single covalent bond, oxygen, or NR_(A);-   X is a single covalent bond, —CR_(A)R_(B)—, —O—, —C(═O)—, —C(═O)O—,    —S(O)_(n)— or —NR_(B)—; and-   R_(y) is:    -   (i) hydrogen; or    -   (ii) C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,        (C₃-C₁₀carbocycle)C₀-C₄alkyl or (3- to 10-membered        heterocycle)C₀-C₄alkyl, each of which is substituted with from 0        to 6 substituents independently selected from R_(x), oxo,        —NH(C₁-C₆alkanoyl), —N(C₁-C₆alkyl)C₁-C₆alkanoyl,        —NHS(O_(n))C₁-C₆alkyl, —N(S(O_(n))C₁-C₆alkyl)₂,        —S(O_(n))NHC₁-C₆alkyl and —S(O_(n))N(C₁-C₆alkyl)₂;-   W is a single covalent bond, —CR_(A)R_(B)—, —NR_(B)— or —O—;-   Z is independently selected at each occurrence from 3- to 7-membered    carbocycles and heterocycles, each of which is substituted with from    0 to 4 substituents independently selected from halogen, oxo, —COOH,    hydroxy, amino, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,    C₁-C₆haloalkoxy, mono- and di-(C₁-C₆alkyl)amino and    —S(O_(n))C₁-C₆alkyl;-   R_(A) and R_(B) are independently selected at each occurrence from:    -   (i) hydrogen; and    -   (ii) C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, saturated or        partially saturated (C₃-C₁₀carbocycle)C₀-C₄alkyl and saturated        or partially saturated (3- to 10-membered        heterocycle)C₀-C₄alkyl, each of which is substituted with from 0        to 6 substituents independently selected from oxo, hydroxy,        halogen, cyano, amino, C₁-C₆alkoxy, mono- and        di-(C₁-C₄alkyl)amino, —COOH, —C(═O)NH₂, —NHC(═O)(C₁-C₆alkyl),        —N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), —NHS(O_(n))C₁-C₆alkyl, SO₃H,        —S(O_(n))C₁-C₆alkyl, C₆alkyl, —S(O_(n))N(C₁-C₆alkyl)C₁-C₆alkyl        and Z;-   R_(C) and R_(D) are independently selected from R_(A), hydroxy,    C₁₋₆alkoxy, and oxo;-   R_(x) is independently chosen at each occurrence from halogen,    hydroxy, amino, cyano, nitro, —COOH, — C(═O)NH₂,    C₁-C₆alkoxycarbonyl, mono- and di-(C₁₋₆alkyl)aminocarbonyl,    C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and    di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl,    C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₂cycloalkyl)C₀-C₄alkyl, and    —S(O_(n))C₁-C₆alkyl;-   m is an integer independently selected at each occurrence from 0-8;    and-   n is an integer independently selected at each occurrence from 0, 1    and 2.

In certain embodiments, C5a receptor modulators provided herein exhibithigh affinity for C5a receptor (i.e., an affinity constant for bindingto C5a receptor of less than 1 micromolar) or very high affinity for C5areceptor (i.e., an affinity constant for binding to the C5a receptor ofless than 100 nanomolar). In certain embodiments, such modulatorsexhibit an affinity for human C5a receptor that is higher than for rator mouse C5a receptor, preferably at least five times higher, morepreferably ten times higher. Affinity of a compound for C5a receptor maybe determined, for example, via a radioligand binding assay, such as theassay provided in Example 14.

Within certain aspects, modulators as described herein are C5a receptorantagonists, such as inverse agonists. Certain such compounds exhibit anEC₅₀ of 1 micromolar or less, 500 nM or less, 100 nM or less, or 25 nMor less, in a standard in vitro C5a receptor-mediated chemotaxis assay(such as the assay provided in Example 9) or a calcium mobilizationassay (as described in Example 16).

Within further aspects, C5a receptor antagonists are essentially free ofC5a receptor agonist activity (i.e., exhibit less than 5% agonistactivity in a GTP binding assay as described in Example 14).

The present invention further provides, within other aspects,pharmaceutical compositions comprising at least one C5a receptormodulator as described herein, in combination with a physiologicallyacceptable carrier or excipient. Processes for preparing suchpharmaceutical compositions are also provided. Such compositions areparticularly useful in the treatment of C5a-mediated inflammation, suchas inflammation associated with various inflammatory and immune systemdisorders.

Within further aspects, methods are provided for inhibitingsignal-transducing activity of a cellular C5a receptor, comprisingcontacting a cell expressing a C5a receptor with at least one C5areceptor modulator as described herein, and thereby reducing signaltransduction by the C5a receptor.

Methods are further provided for inhibiting binding of C5a to C5areceptor in vitro, comprising contacting C5a receptor with at least oneC5a receptor modulator as described herein, under conditions and in anamount sufficient to detectably inhibit C5a binding to C5a receptor.

The present invention further provides methods for inhibiting binding ofC5a to C5a receptor in a human patient, comprising contacting cellsexpressing C5a receptor with at least one C5a receptor modulator asdescribed herein.

Within further aspects, the present invention provides methods fortreating a patient in need of anti-inflammatory treatment orimmunomodulatory treatment. Such methods generally compriseadministering to the patient a therapeutically effective amount of a C5areceptor modulator as described herein. Treatment of humans,domesticated companion animals (pets) or livestock animals sufferingsuch conditions is contemplated by the present invention. In certainsuch aspects, methods are provided for treating a patient suffering fromcystic fibrosis, rheumatoid arthritis, psoriasis, cardiovasculardisease, reperfusion injury, or bronchial asthma comprisingadministering to the patient a therapeutically effective amount of a C5areceptor modulator as described herein. In further such aspects, methodsare provided for treating a patient suffering from stroke, myocardialinfarction, atherosclerosis, ischemic heart disease, orischemia-reperfusion injury comprising administering to the patient atherapeutically effective amount of a C5a receptor modulator asdescribed herein.

The present invention further provides methods for inhibiting C5areceptor-mediated cellular chemotaxis (preferably leukocyte (e.g.,neutrophil) chemotaxis), comprising contacting mammalian white bloodcells with a therapeutically effective amount of a C5a receptormodulator as described herein. In certain embodiments, the white bloodcells are primate white blood cells, such as human white blood cells.

Within further aspects, the present invention provides methods for usinga C5a receptor modulator as described herein as a probe for thelocalization of receptors, particularly C5a receptors. Such localizationmay be achieved, for example, in tissue sections (e.g., viaautoradiography) or in vivo (e.g., via positron emission tomography,PET, or single positron emission computed tomography, SPECT, scanningand imaging). Within certain such aspects, the present inventionprovides methods for localizing C5a receptors in a tissue sample,comprising: (a) contacting the tissue sample containing C5a receptorswith a detectably labeled compound as described herein under conditionsthat permit binding of the compound to C5a receptors; and (b) detectingthe bound compound. Such methods may, optionally, further comprise astep of washing the contacted tissue sample, prior to detection.Suitable detectable labels include, for example, radiolabels such as¹²⁵I, tritium, ¹⁴C, ³²P and ⁹⁹Tc.

The present invention also provides packaged pharmaceuticalpreparations, comprising: (a) a pharmaceutical composition as describedherein in a container; and (b) instructions for using the composition totreat a patient suffering from one or more conditions responsive to C5areceptor modulation, such as rheumatoid arthritis, psoriasis,cardiovascular disease, reperfusion injury, bronchial asthma, stroke,myocardial infarction, atherosclerosis, ischemic heart disease, orischemia-reperfusion injury.

In yet another aspect, the present invention provides methods forpreparing the compounds disclosed herein, including the intermediates.

These and other aspects of the present invention will become apparentupon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention provides 3-aryl-5,6-disubstitutedpyridazines that modulate C5a receptor activation and/or C5areceptor-mediated signal transduction. Such compounds may be used invitro or in vivo to modulate (preferably inhibit) C5a receptor activityin a variety of contexts.

Chemical Description and Terminology

Compounds are generally described herein using standard nomenclature.For compounds having asymmetric centers, it should be understood that(unless otherwise specified) all of the optical isomers and mixturesthereof are encompassed. Compounds with two or more asymmetric elementscan also be present as mixtures of diastereomers. In addition, compoundswith carbon-carbon double bonds may occur in Z- and E-forms, with allisomeric forms of the compounds being included in the present inventionunless otherwise specified. Where a compound exists in varioustautomeric forms, a recited compound is not limited to any one specifictautomer, but rather is intended to encompass all tautomeric forms.Recited compounds are further intended to encompass compounds in whichone or more atoms are replaced with an isotope (i.e., an atom having thesame atomic number but a different mass number). By way of generalexample, and without limitation, isotopes of hydrogen include tritiumand deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

Certain compounds are described herein using a general formula thatincludes variables (e.g., R₁-R₅, R₈-R₁₃, Ar). Unless otherwisespecified, each variable within such a formula is defined independentlyof any other variable, and any variable that occurs more than one timein a formula is defined independently at each occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R*, the groupmay be unsubstituted or substituted with up to two R* groups and R* ateach occurrence is selected independently from the definition of R*.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

The term “3-aryl-5,6-disubstituted pyridazines,” as used herein, refersto compounds of Formula I, Formula II and/or other Formula(s) providedherein, as well as pharmaceutically acceptable salts thereof. It will beapparent that such compounds may be further substituted as indicated(e.g., 3-aryl-4,5,6-trisubstituted pyridazines and 1-aryl-4-substitutedphthalazines are encompassed by the term “3-aryl-5,6-disubstitutedpyridazines”).

A “pharmaceutically acceptable salt” of a compound recited herein is anacid or base salt that is generally considered in the art to be suitablefor use in contact with the tissues of human beings or animals withoutexcessive toxicity or carcinogenicity, and preferably withoutirritation, allergic response, or other problem or complication. Suchsalts include mineral and organic acid salts of basic residues such asamines, as well as alkali or organic salts of acidic residues such ascarboxylic acids. Specific pharmaceutical salts include, but are notlimited to, salts of acids such as hydrochloric, phosphoric,hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic,formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethanedisulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic,citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic,pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic,phenylacetic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where n is0-4, and the like. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those of ordinary skill in the art will recognizefurther pharmaceutically acceptable salts for the compounds providedherein, including those listed by Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). Ingeneral, a pharmaceutically acceptable acid or base salt can besynthesized from a parent compound that contains a basic or acidicmoiety by any conventional chemical method. Briefly, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, the use ofnonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol oracetonitrile, is preferred.

It will be apparent that each compound of Formula I or Formula II(and/or other Formula(s) provided herein) may, but need not, beformulated as a hydrate, solvate or non-covalent complex. In addition,the various crystal forms and polymorphs are within the scope of thepresent invention, as are prodrugs of the compounds of the Formulasprovided herein. A “prodrug” is a compound that may not fully satisfythe structural requirements of the compounds provided herein, but ismodified in vivo, following administration to a patient, to produce acompound of Formula I, Formula II or other formula provided herein. Forexample, a prodrug may be an acylated derivative of a compound asprovided herein. Prodrugs include compounds wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to amammalian subject, cleaves to form a free hydroxy, amino, or sulfhydrylgroup, respectively. Examples of prodrugs include, but are not limitedto, acetate, formate, phosphate and benzoate derivatives of alcohol andamine functional groups within the compounds provided herein. Prodrugsof the compounds provided herein may be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved in vivo to generate the parent compounds.

A “therapeutically effective amount” (or dose) is an amount that, uponadministration to a patient, results in a discernible patient benefit(e.g., provides detectable relief from a condition being treated). Suchrelief may be detected using any appropriate criteria, includingalleviation of one or more symptoms. A therapeutically effective amountor dose generally results in a concentration of compound in a body fluid(such as blood, plasma, serum, CSF, synovial fluid, lymph, cellularinterstitial fluid, tears or urine) that is sufficient to inhibitchemotaxis of white blood cells in an in vitro assay and/or alter C5areceptor activity or activation as measured by an in vitro calciummobilization assay. It will be apparent that the discernible patientbenefit may be apparent after administration of a single dose, or maybecome apparent following repeated administration of the therapeuticallyeffective dose according to a predetermined regimen, depending upon theindication for which the compound is administered.

A “substituent,” as used herein, refers to a molecular moiety that iscovalently bonded to an atom within a molecule of interest. For example,a “ring substituent” may be a moiety such as a halogen, alkyl group,haloalkyl group or other substituent described herein that is covalentlybonded to an atom (preferably a carbon or nitrogen atom) that is a ringmember. The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated substituents; provided that the designated atom's normalvalence is not exceeded, and that the substitution results in a stablecompound (i.e., a compound that can be isolated, characterized andtested for biological activity). When a substituent is oxo (i.e., =0),then 2 hydrogens on the atom are replaced. An oxo group that is asubstituent of an aromatic carbon atom results in a conversion of —CH—to —C(═O)— and a loss of aromaticity. For example a pyridyl groupsubstituted by oxo is a pyridone.

The phrase “optionally substituted” indicates that a group may either beunsubstituted or substituted at one or more of any of the availablepositions, typically 1, 2, 3, 4, or 5 positions, by one or more suitablesubstituents such as those disclosed herein. Optional substitution mayalso be indicated by the phrase “substituted with from 0 to Xsubstituents,” in which X is the maximum number of substituents.

Suitable substituents include, for example, halogen, cyano, amino,hydroxy, nitro, azido, CONH₂, —COOH, SO₂NH₂, alkyl (e.g., C₁-C₈alkyl),alkenyl (e.g., C₂-C₈alkenyl), alkynyl (e.g., C₂-C₈alkynyl), alkoxy(e.g., C₁-C₈alkoxy), alkyl ether (e.g., C₂-C₈alkyl ether), alkylthio(e.g., C₁-C₈alkylthio), haloalkyl (e.g., C₁-C₈haloalkyl), hydroxyalkyl(e.g., C₁-C₈hydroxyalkyl), aminoalkyl (e.g., C₁-C₈aminoalkyl),haloalkoxy (e.g., C₁-C₈haloalkoxy), alkanoyl (e.g., C₁-C₈alkanoyl),alkanone (e.g., C₁-C₈alkanone), alkanoyloxy (e.g., C₁-C₈alkanoyloxy),alkoxycarbonyl (e.g., C₁-C₈alkoxycarbonyl), mono- anddi-(C₁-C₈alkyl)amino, mono- and di-(C₁-C₈alkyl)aminoC₁-C₈alkyl, mono-and di-(C₁-C₈alkyl)aminocarbonyl, mono- and di-(C₁-C₈alkyl)sulfonamido,alkylsulfinyl (e.g., C₁-C₈alkylsulfinyl), alkylsulfonyl (e.g.,C₁-C₈alkylsulfonyl), aryl (e.g., phenyl), arylalkyl (e.g.,(C₆-C₁₈aryl)C₁-C₈alkyl, such as benzyl and phenethyl), aryloxy (e.g.,C₆-C₁₈aryloxy such as phenoxy), arylalkoxy (e.g.,(C₆-C₁₈aryl)C₁-C₈alkoxy) and/or 3- to 8-membered heterocyclic groupssuch as coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl,pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl,benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, morpholino or pyrrolidinyl. Certain groups within theformulas provided herein are optionally substituted with from 1 to 3, 1to 4 or 1 to 5 independently selected substituents.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, and wherespecified, having the specified number of carbon atoms. Thus, the term“C₁-C₈alkyl” (or “C₁₋₆alkyl”), as used herein, indicates an alkyl grouphaving from 1 to 6 carbon atoms. “C₀-C₄alkyl” refers to a singlecovalent bond (C₆alkyl) or a C₁-C₄alkyl group. Alkyl groups includegroups having from 1 to 8 carbon atoms (C₁-C₈alkyl), from 1 to 6 carbonatoms (C₁-C₆alkyl) and from 1 to 4 carbon atoms (C₁-C₄alkyl), such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. In certain embodiments, preferred alkyl groups aremethyl, ethyl, propyl, butyl, and 3-pentyl. “Aminoalkyl” is an alkylgroup as defined herein substituted with one or more —NH₂ substituents.“Hydroxyalkyl” is a hydroxy group as defined herein substituted with oneor more —OH substituents.

“Alkylene” refers to a divalent alkyl group, as defined above.C₀-C₄alkylene is a single covalent bond or an alkylene group having from1 and 4 carbon atoms.

“Alkenyl” refers to a straight or branched hydrocarbon chain comprisingone or more unsaturated carbon-carbon bonds, such as ethenyl andpropenyl. Alkenyl groups include C₂-C₈alkenyl, C₂-C₆alkenyl andC₂-C₄alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbonatoms, respectively), such as ethenyl, allyl or isopropenyl.

“Alkynyl” refers to straight or branched hydrocarbon chains comprisingone or more triple carbon-carbon bonds. Alkynyl groups includeC₂-C₈alkynyl, C₂-C₆alkynyl and C₂-C₄alkynyl groups, which have from 2 to8, 2 to 6 or 2 to 4 carbon atoms, respectively. Alkynyl groups includefor example groups such as ethynyl and propynyl.

By “alkoxy,” as used herein, is meant an alkyl, alkenyl or alkynyl groupas described above attached via an oxygen bridge. Alkoxy groups includeC₁-C₆alkoxy and C₁-C₄alkoxy groups, which have from 1 to 6 or 1 to 4carbon atoms, respectively. Methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxyare representative alkoxy groups. Similarly “alkylthio” refers to analkyl, alkenyl or alkynyl group as described above attached via a sulfurbridge.

The term “alkanoyl” refers to an alkyl group as defined above attachedthrough a carbonyl bridge. Alkanoyl groups include C₂-C₈alkanoyl,C₂-C₆alkanoyl and C₂-C₄alkanoyl groups, which have from 2 to 8, 2 to 6or 2 to 4 carbon atoms, respectively. “C₁alkanoyl” refers to —(C═O)—H,which (along with C₂-C₈alkanoyl) is encompassed by the term“C₁-C₈alkanoyl.” Ethanoyl is C₂alkanoyl.

An “alkanone” is an alkyl group as defined above with the indicatednumber of carbon atoms substituted at least one position with an oxogroup. “C₃-C₈alkanone,” “C₃-C₆alkanone” and “C₃-C₄alkanone” refer to analkanone having from 3 to 8, 6 or 4 carbon atoms, respectively. By wayof example, a C₃ alkanone group has the structure —CH₂—(C═O)—CH₃.

Similarly, “alkyl ether” refers to a linear or branched ethersubstituent linked via a carbon-carbon bond. Alkyl ether groups includeC₂-C₈alkyl ether, C₂-C₆alkyl ether and C₂-C₄alkyl ether groups, whichhave 2 to 8, 6 or 4 carbon atoms, respectively. By way of example, aC₂alkyl ether group has the structure —CH₂—O—CH₃.

The term “alkoxycarbonyl” refers to an alkoxy group attached through aketo (—(C═O)—) bridge (i.e., a group having the general structure—C(═O)—O-alkyl). Alkoxycarbonyl groups include C₁-C₈, C₁-C₆ andC₁-C₄alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms,respectively, in the alkyl portion of the group (i.e., the carbon of theketo bridge is not included in the indicated number of carbon atoms).“C₁alkoxycarbonyl” refers to —C(═O)—O—CH₃; C₃alkoxycarbonyl indicates—C(═O)—O—(CH₂)₂CH₃ or —C(═O)—O—(CH)(CH₃)₂.

“Alkanoyloxy,” as used herein, refers to an alkanoyl group linked via anoxygen bridge (e.g., a group having the general structure—O—C(═O)-alkyl). Alkanoyloxy groups include C₁-C₈, C₁-C₆ andC₁-C₄alkanoyloxy groups, which have from 1 to 8, 6 or 4 carbon atoms,respectively, in the alkyl portion fo the group.

“Alkylamino” refers to a secondary or tertiary amine having the generalstructure —NH-alkyl or —N(alkyl)(alkyl), wherein each alkyl may be thesame or different. Such groups include, for example, mono- anddi-(C₁-C₈alkyl)amino groups, in which each alkyl may be the same ordifferent and may contain from 1 to 8 carbon atoms, as well as mono- anddi-(C₁-C₈alkyl)amino groups and mono- and di-(C₁-C₄alkyl)amino groups.“Mono- or di-(C₁-C₄alkylamino)C₀-C₄alkyl” refers to a mono- anddi-(C₁-C₄alkyl)amino group that is linked via a single covalent bond(C₀alkyl) or a C₁-C₄alkylene group (i.e., a group having the generalstructure —C₀-C₄alkyl-NH—(C₁-C₄alkyl) or —C₀-C₄alkyl-N(C₁-C₄alkyl)₂, inwhich each alkyl may be the same or different. Similarly, “mono- ordi-(C₁-C₄alkyl)aminoC₁-C₄alkoxy” refers to an alkylamino group linkedvia an alkoxy group (i.e., a group of the formula—O—(C₁-C₄alkyl)-NH(C₁-C₄alkyl) or —O—(C₁-C₄alkyl)-N(C₁-C₄alkyl)₂.

“(C₁-C₆alkyl)(2-acetamide)amino” refers to an amino group in which onehydrogen is replaced with C₁-C₆alkyl and the other hydrogen is replacedwith a 2-acetamide group.

The term “aminocarbonyl” refers to an amide group (i.e., —(C═O)NH₂).“Mono- or di-(C₁-C₆alkyl)aminocarbonyl” refers to an amide group inwhich one or both of the hydrogen atoms is replaced with anindependently chosen C₁-C₆alkyl. Such groups may also be indicated by“—C(═O)NH(alkyl)” or “—C(═O)N(alkyl)(alkyl).”

The term “halogen” refers to fluorine, chlorine, bromine and iodine. A“haloalkyl” is a branched or straight-chain alkyl group, substitutedwith 1 or more halogen atoms (e.g., “haloC₁-C₈alkyl” groups have from 1to 8 carbon atoms; “haloC₁-C₈alkyl” groups have from 1 to 6 carbonatoms). Examples of haloalkyl groups include, but are not limited to,mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-,di-, tri-, tetra- or penta-fluoroethyl; and mono-, tri-, tetra- orpenta-chloroethyl. Typical haloalkyl groups are trifluoromethyl anddifluoromethyl. Within certain compounds provided herein, not more than5 or 3 haloalkyl groups are present. The term “haloalkoxy” refers to ahaloalkyl group as defined above attached via an oxygen bridge.“HaloC₁-C₈alkoxy” groups have 1 to 8 carbon atoms.

A “carbocycle” is any saturated, partially saturated, or aromatic grouphaving 1 or 2 fused, pendant or spiro rings, with 3 to 8 atoms in eachring, and with all ring members being carbon. The term “carbocycle”encompasses aromatic groups such as phenyl and naphthyl, as well asgroups that comprise both aromatic and nonaromatic rings (e.g.,tetrahydronaphthyl), and groups with saturated and partially saturatedrings (such as cyclohexyl and cyclohexenyl). When substitutions areindicated, carbocycles may be substituted on any ring atom where suchsubstitution results in a stable compound. The term “C₃-C₁₀carbocycle”refers to such groups having from 3 to 10 ring members. A“(C₃-C₁₀carbocycle)C₀-C₄alkyl” group is a C₃-C₁₀carbocycle that islinked via a single covalent bond or a C₁-C₄alkylene group.

Certain carbocycles are “cycloalkyl” (i.e., a saturated or partiallysaturated carbocycle). Such groups typically contain from 3 to about 8ring carbon atoms; in certain embodiments, such groups have from 3 to 7ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, as well as such groups modifiedby the presence of one or more double or triple bonds (e.g.,cyclohexenyl) and bridged or caged saturated ring groups such asnorbornane or adamantane. If substituted, any ring carbon atom may bebonded to any indicated substituent.

In the term “(cycloalkyl)alkyl”, “cycloalkyl” and “alkyl” are as definedabove, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyland cyclohexylethyl. “(C₃-C₂cycloalkyl)C₀-C₄alkyl” refers to 3- to7-membered cycloalkyl rings that are linked via a single covalent bondor a C₁-C₄alkylene.

Similarly, “(cycloalkyl)alkoxy” refers to a cycloalkyl group linked viaan alkoxy group (i.e., a group of the formula O-alkyl-cycloalkyl).

“Cycloalkoxy” refers to a cycloalkyl as described above linked via anoxygen bridge (e.g., cyclopentyloxy or cyclohexyloxy).

Other carbocycles are “aryl” (i.e., carbocycles that comprise at leastone aromatic ring). In addition to the aromatic ring(s), additionalnon-aromatic ring(s) may be present in an aryl group. Representativearyl groups include phenyl, naphthyl (e.g., 1-naphthyl and 2-naphthyl),biphenyl, tetrahydronaphthyl and indanyl.

The term “arylalkyl” refers to an aryl group that is linked via analkylene group. Certain arylalkyl groups are arylC₀-C₂alkyl, in which anaryl group is linked via a single covalent bond or a methylene orethylene moiety. Such groups include, for example, groups in whichphenyl or naphthyl is linked via a bond or C₁-C₂alkyl, such as benzyl,1-phenyl-ethyl and 2-phenyl-ethyl.

The term “aryloxy” refers to an aryl group linked via a an oxygen (i.e.,a group having the general structure —O-aryl). Phenoxy is arepresentative aryloxy group.

The term “arylalkoxy” refers to an aryl group linked via an alkoxy group(i.e., a group having the general structure —O-alkyl-aryl).

A “heteroatom” is an atom other than carbon, such as oxygen, sulfur ornitrogen.

The term “heterocycle” or “heterocyclic group” is used to indicatesaturated, partially unsaturated, or aromatic groups having 1 or 2fused, pendent or spiro rings, with 3 to 8 atoms in each ring, and in atleast one ring from 1 to 4 heteroatoms independently selected from N, Oand S, with remaining atoms being carbon. Certain heterocycles are 3- to10-membered monocyclic or bicyclic groups; other are 4- to 6-memberedmonocyclic groups. The heterocyclic ring may be attached at anyheteroatom or carbon atom that results in a stable structure, and may besubstituted on carbon and/or nitrogen atom(s) if the resulting compoundis stable. Any nitrogen and/or sulfur heteroatoms may optionally beoxidized, and any nitrogen may optionally be quaternized.

Variations on the term “(heterocycle)alkyl” refer to a heterocycle thatis linked via a single covalent bond or alkylene group. Such groupsinclude, for example, (3- to 10-membered heterocycle)C₀-C₄alkyl groups,in which the heterocycle contains from 3 to 10 ring members and islinked via a single covalent bond or C₁-C₄alkyl. Unless otherwisespecified, the heterocycle portion of such groups may be saturated,partially saturated or aromatic. “(4- to 6-memberedheterocycloalkyl)C₀-C₄alkyl” refers to a heterocycloalkyl group of from4 to 6 ring members that is linked via a single covalent bond or aC₁-C₄alkylene.

Certain heterocycles are “heteroaryl” (i.e., groups that comprise atleast one aromatic ring having from 1 to 4 heteroatoms). When the totalnumber of S and 0 atoms in a heteroaryl group exceeds 1, then theseheteroatoms are not adjacent to one another; preferably the total numberof S and 0 atoms in a heteroaryl is not more than 1, 2 or 3, morepreferably 1 or 2 and most preferably not more than 1. Examples ofheteroaryl groups include pyridyl, furanyl, indolyl, pyrimidinyl,pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl,triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinoline.

Other heterocycles are referred to herein as “heterocycloalkyl” (i.e.,saturated or partially saturated heterocycles). Heterocycloalkyl groupshave 1 or 2 rings, each with from 3 to about 8 ring atoms, and moretypically from 5 to 7 ring atoms. Examples of heterocycloalkyl groupsinclude morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl.

Additional examples of heterocyclic groups include, but are not limitedto, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“A C5a receptor” is a G-protein coupled receptor that specifically bindsC5a peptide. Certain preferred C5a receptors are human, such as theprotein product of the sequence that produces the human C5a receptor PCRproduct described by Gerard and Gerard (1991) Nature 349:614-17. Thehuman C5a receptor may also be that described by Boulay (1991)Biochemistry 30(12):2993-99 (nucleotide sequence encoding the receptoris available at GENBANK Accession No. M62505). Non-primate C5a receptorsinclude the rat C5a receptor (encoded by the nucleotide sequence havingGENBANK Accession No. X65862, Y09613 or AB003042), canine C5a receptor(encoded by the nucleotide sequence having GENBANK Accession No.X65860), and guinea pig C5a receptor (encoded by the nucleotide sequencehaving GENBANK Accession No. U86103).

A “C5a receptor modulator” (also referred to herein as a “modulator”) isany compound that modulates C5a receptor activation and/or activity(i.e., C5a receptor-mediated signal transduction, as measured using aC5a receptor-mediated chemotaxis, or calcium mobilization assay asprovided herein). In certain embodiments, such a modulator may beexhibit an affinity constant for binding to a C5a receptor of less than1 micromolar in a standard C5a receptor radioligand binding assay;and/or an EC₅₀ of less than 1 micromolar in a standard C5areceptor-mediated chemotaxis assay or calcium mobilization assay. Inother embodiments the a C5a receptor modulator may exhibit an affinityconstant or EC₅₀ of less than 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10nM or 5 nM in such an assay. A modulator may be a C5a receptor agonistor antagonist, although, for certain purposes described herein, amodulator preferably inhibits C5a activation resulting from binding ofC5a (i.e., the modulator is an antagonist). In addition, oralternatively, a modulator may act as an inverse agonist of C5areceptor. In certain embodiments, modulators provided herein modulateactivation and/or activity of a primate C5a receptor, such as human C5areceptor, which may be a cloned, recombinantly expressed receptor or anaturally expressed receptor. For treating non-human animals of anyparticular species, a compound exhibiting high affinity for C5a receptorof that particular species is preferred.

Certain C5a receptor modulators exhibit high activity in a standard invitro C5a receptor mediated chemotaxis assay, as specified in Example 9,herein. Such compounds exhibit an EC₅₀ of 4 μM or less in such astandard C5a mediated chemotaxis assay, preferably an EC₅₀ of 1 μM orless in such an assay, more preferably an EC₅₀ of 0.1 μM or less in suchan assay, and even more preferably and EC₅₀ of 10 nM or less in such anassay.

An “inverse agonist” of a C5a receptor is a compound that reduces theactivity of C5a receptor below its basal activity level in the absenceof added C5a. Inverse agonists may also inhibit the activity of C5a atC5a receptor, and/or may inhibit binding of C5a to C5a receptor. Theability of a compound to inhibit the binding of C5a to C5a receptor maybe measured by a binding assay, such as the radioligand binding assaygiven in Example 14. The basal activity of C5a receptor may bedetermined from a GTP binding assay, such as the assay of Example 15.The reduction of C5a receptor activity may also be determined from a GTPbinding assay or a calcium mobilization assay such as the assay ofExample 15.

A “neutral antagonist of C5a receptor is a compound which inhibits theactivity of C5a at C5a receptor, but does not significantly change thebasal activity of C5a receptor. Neutral antagonists of C5a receptor mayinhibit the binding of C5a to C5a receptor.

A “partial agonist” of C5a receptor elevates the activity of C5areceptor above the basal activity level of the receptor in the absenceof C5a, but does not elevate the activity of C5a receptor to the levelbrought about by saturating levels of the natural agonist, C5a. Partialagonist compounds may inhibit the binding of C5a to C5a receptor.Partial agonists of C5a receptor usually elevate the activity of C5areceptor, producing a level of elevation ranging from 5% to 90% of theactivity level brought about by receptor-saturating concentrations ofthe natural agonist, C5a.

C5a Receptor Modulators

As noted above, the present invention provides 3-aryl-5,6-disubstitutedpyridazines of Formulas I and II that may be used to alter C5a receptoractivity in a variety of contexts, including in the treatment ofpatients suffering from diseases or disorders responsive to C5a receptormodulation, such as autoimmune disorders and inflammatory conditions.C5a receptor modulators may also be used within a variety of in vitroassays (e.g., assays for receptor activity), as probes for detection andlocalization of C5a receptor and as standards in assays of ligandbinding and C5a receptor-mediated signal transduction.

Certain compounds of Formula I or II, include those in which R₁ ishydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or (C₃-C₇cycloalkyl)-C₀-C₄alkyl. Othercompounds of Formula I or II include those in which R₁ is hydrogen,C₁-C₁alkyl or C₁-C₄alkoxy, or compounds of Formula II in which R₁ ishydrogen, methyl, ethyl, or methoxy.

Other compounds of Formula I or II, include those in which R₃ isC₃₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, mono- anddi-(C₁₋₆alkyl)amino, (amino)C₀₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkoxy,or 3 to 7 membered heterocyclic groups, each of which may be substitutedwith 0 to 4 R_(x) groups. In other compounds of Formula I or II, R₃ ishydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, or C₃₋₇cycloalkyl each of which issubstituted with 0 or 1 R_(x) groups. R_(x) is independently chosen ateach occurrence from halogen, hydroxy, amino, cyano, nitro, —COOH,—C(═O)NH₂, SO₂NH₂, C₁-C₆alkoxycarbonyl, mono- anddi-(C₁₋₆alkyl)aminocarbonyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and—S(O_(n))C₁-C₆alkyl.

In certain compounds of Formula I or II, R₁ and R₃, taken incombination, form an optionally substituted fused benzo ring. In certainother compounds of Formula I or II, R₁ and R₃, taken in combination forman fused benzo ring substituted with between 0-2 R_(x) groups, whereinR_(x) is independently selected at each occurrence from the groupconsisting of halogen, hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH₂,SO₂NH₂, C₁-C₆alkoxycarbonyl, mono- and di-(C₁₋₆alkyl)aminocarbonyl,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino,C₁-C₆alkoxy, C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, and —S(O_(n))C₁-C₆alkyl.

Yet other compounds of Formula I or II, include those in which R₄ is:

-   -   (i) C₂-C₃alkyl, C₂-C₈alkenyl, C₂-C₃alkynyl,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or        di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered        heterocycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl,        pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl,        imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl,        benzoisothiazolyl or tetrahydronapthyl, each of which is        substituted with from 0 to 4 substituents independently chosen        from R_(x), C₂-C₄alkanoyl, mono- and        di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and        di-C₁-C₄alkylamino(C₁-C₄alkoxy), or (3- to 7-membered        heterocycloalkyl)C₀-C₄alkyl and XR_(y); or    -   (ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅        are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring        members in each ring, wherein the heterocycle is substituted        with from 0 to 4 substituents independently chosen from R_(x),        oxo and W—Z; and

-   R₅ is:    -   (i) hydrogen;    -   (ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or        (C₃-C₇carbocycle)C₀-C₄alkyl, each of which is substituted with        from 0 to 3 substituents independently chosen from halogen,        hydroxy, amino, cyano, C₁-C₄alkoxy, methylamino, dimethylamino,        trifluoromethyl and trifluoromethoxy; or    -   (iii) joined to R₄ to form an optionally substituted        heterocycle.

In certain other compounds of Formula I or II, Ar is ortho-substitutedphenyl, having between 0 and 2 additional substituents, optionallysubstituted naphthyl, or optionally substituted heteroaryl. In certainother compounds of Formula I or II, Ar is ortho-substituted phenyl,1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl,thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl,isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each ofwhich is optionally mono-, di-, or tri-substituted.

In yet other compounds of Formula I or II, Ar is ortho-substitutedphenyl substituted with between 0 and 2 additional residues, whereineach substituent is independently selected from the group consisting ofoptionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆alkenyl,optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆alkoxy,optionally substituted (C₁₋₆alkoxy)C₁₋₆alkyl, optionally substituted(amino)C₁₋₆alkyl, optionally substituted mono- and di-(C₁₋₆alkyl)amino.

Certain compounds of Formula II include those in which A is NR₄R₅ andare referred to herein as compounds of Formula II-a. Certain compoundsof Formula II-a include those in which: R₄ is chosen from(C₃-C₇cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl,pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl,pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl, indazolylC₀-C₄alkyl,benzocycloalkenylC₀-C₁alkyl, decahydronaphthylC₀-C₄alkyl,benzoisothiazolylC₀-C₄alkyl, tetrahydroquinolinylC₀-C₄alkyl andtetrahydronaphthylC₀-C₄alkyl, each of which is substituted with from 0to 4 groups independently chosen from R_(x), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl, C₂-C₄alkanoyl and C₂-C₄alkanoyloxy; and R₅is C₁-C₆alkyl, C₂-C₆alkenyl or (C₃-C₇-carbocycle)C₀-C₄alkyl.

In other compounds of Formula II-a provided herein include those inwhich R₄ and R₅ are joined to form a form a saturated or partiallysaturated heterocycle containing 1 or 2 fused or Spiro rings; whereinthe heterocycle is substituted with from 0 to 4 substituentsindependently chosen from halogen, hydroxy, amino, cyano, —COOH,—CH₂COOH, C₁₋₆alkoxycalbonyl, —CH₂CO₂—C₁₋₆alkyl, —C(═O)NH₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—S(O_(n))C₁-C₆alkyl, SO₃H, optionally substituted phenyl, optionallysubstituted phenoxy, optionally substituted pyridyl, and optionallysubstituted pyridyloxy. More preferably, R₄ and R₅ are joined to form asaturated 4- to 7-membered heterocyclic ring that is substituted withfrom 0 to 3 substituents independently chosen from halogen, hydroxy,amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, difluoromethyl,trifluoromethoxy difluoromethoxy, —COOH, —CH₂COOH, C₁₋₂alkoxycarbonyl,—CH₂CO₂—C₁₋₂alkyl, phenyl substituted with 0-3 R_(x) groups, optionallysubstituted phenoxy. Certain compounds of Formula II-a include those inwhich R₄ and R₅ are combined to form an azepanyl, morpholinyl,homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl,piperidinyl, homopiperidinyl, and the like.

In certain other compounds of Formula II-a in which R₄ and R₅ arecombined to form a heterocycle, the heterocycle comprises 2 rings;wherein each of the rings is substituted with from 0 to 3 substituentsindependently selected from the group consisting of halogen, hydroxy,amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, difluoromethyl,trifluoromethoxy, and difluoromethoxy. Certain compounds of Formula II-ain which R₄ and R₅ are combined to form a bicyclic heterocycle includethose in which the heterocycle is tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl,indazolyl, indolinyl, phenylimidazolyl, pyridooxazinyl, benzoxazinyl, orthe like.

The invention provides compounds Formula II and pharmaceutical saltsthereof, wherein the compound is according to Formula III:

wherein:

-   R₇ represents between 0 and 2 substituents independently selected    from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,    C₁₋₆haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x); and    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₂cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; and-   G is CH₂, CHR₁₃, sulfur, oxygen or NR_(E); wherein R_(E) is:    -   (i) hydrogen; or        -   (ii) C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenyl or a 5-            or 6-membered heteroalyl ring, each of which is substituted            with from 0 to 3 substituents independently chosen from            R_(x). In certain compounds R₇ is absent. In yet other            compounds of Formula III, G is oxygen.

In other compounds of Formula III, R₁₃ represents from 0 to 2substituents independently chosen from halogen, methyl, methoxy, ethyl,phenyl, and phenoxy, wherein each phenyl or phenoxy group is substitutedwith between 0 and 3 substituents independently chosen from R.

Certain compounds of Formula II-a include compounds or pharmaceuticallyacceptable salts thereof according to Formula (IV):

wherein:

-   R₇ represents between 0 and 2 substituents independently selected    from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,    C₁₋₆haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;-   R₁₀ and R₁₁ are independently chosen from hydrogen, C₁-C₆alkyl,    C₁-C₂haloalkyl and C₃-C₇cycloalkyl(C₀-C₂alkyl); and-   R₁₂ represents from 0 to 3 substituents independently chosen from    R_(x), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and    di-(C₁-C₄alkyl)amino(C₁-C₄alkoxy) and YZ; or two adjacent R₁₂ groups    are joined to form a fused 5- to 7-membered carbocyclic or    heterocyclic ring. In certain compounds of Formula IV R₇ is absent.

The invention provides certain compounds of Formula IV include those inwhich R₁₂ represents from 0 to 3 substituents independently chosen fromhalogen, hydroxy, amino, cyano, C₁-C₄alkyl, mono- anddi-(C₁-C₂alkyl)amino, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and(C₃-C₇cycloalkyl)C₀-C₂alkyl.

Other compounds of Formula IV include those in which:

-   R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy,    C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and-   Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl, pyridyl,    pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,    imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl,    pyrrolyl, furanyl, and triazolyl, each of which is optionally mono-,    di-, or tri-substituted.

Other compounds of Formula II-a include compounds or pharmaceuticallyacceptable salts thereof according to Formula (V):

wherein:

-   R₇ represents between 0 and 2 substituents independently selected    from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,    C₁₋₆haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;-   R₁₂ represents from 0 to 3 substituents independently chosen from    R_(x), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and    di-(C₁-C₄alkyl)amino(C₁-C₄alkoxy) and YZ; or two adjacent R₁₂ groups    are joined to form a fused 5- to 7-membered carbocyclic or    heterocyclic ring.-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x);    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; or    -   (iii) two R₁₃ residues, taken in combination, form a fused        benzene ring which is substituted with from 0 to 4 substituents        independently chosen from halogen, hydroxy, COOH, CONH₂, SO₂NH₂,        amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,        and mono- and di-(C₁-C₄alkyl)amino;-   R₁₄ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    C₁-C₂haloalkyl or (C₃-C₇cycloalkyl)C₀-C₂alkyl, COOH, CONH₂, CH₂COOH,    CH₂CONH₂, C₃₋₆alkoxycarbonyl, CH₂CO₂—C₁₋₆alkyl, or SO₃H; and-   x is 0, 1 or 2.

In certain compounds of Formula V R₇ is absent. In other compounds ofFormula V, x is 1.

Certain compounds of Formula V include those in which R₁₂ and R₁₃independently represent from 0 to 2 substituents independently chosenfrom halogen, methyl, methoxy and ethyl; and R₁₄ is hydrogen,C₁-C₆alkyl, C₂-C₆alkenyl or C₃-C₇cycloalkyl(C₀-C₂alkyl).

The invention provides certain compounds of Formula V include those inwhich:

-   R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy,    C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and    C₁-C₆alkoxy; and-   Ar is ortho-substituted phenyl which is mono-, di-, or    tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl,    pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl,    tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, indolyl,    indazolyl, and triazolyl, each of which is optionally mono-, di-, or    tri-substituted.

Yet other compounds of Formula II-a include compounds orpharmaceutically acceptable salts thereof according to Formula (VI):

wherein:

-   R₇ represents between 0 and 2 substituents independently selected    from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,    C₁₋₆haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;-   R₁₂ represents from 0 to 3 substituents independently chosen from    R_(x), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and    di-(C₁-C₄alkyl)amino(C₁-C₄alkoxy) and YZ; or two adjacent R₁₂ groups    are joined to form a fused 5- to 7-membered carbocyclic or    heterocyclic ring.-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x);    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; or    -   (iii) two R₁₃ residues, taken in combination, form a fused        benzene ring which is substituted with from 0 to 4 substituents        independently chosen from halogen, hydroxy, COOH, CONH₂, SO₂NH₂,        amino, cyano, (C₃-C₂cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl,        C₁-C₂haloalkoxy, and mono- and di-(C₁-C₄alkyl)amino;-   G is CH₂, NH, sulfur or oxygen;-   G₃ is N, CH, or CR_(x), and-   x is 0, 1 or 2.

Other compounds of Formula II-a provided herein include those whichsatisfy Formula VII

wherein

-   R₇ represents between 0 and 2 substituents independently selected    from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,    C₁₋₆haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;-   R₁₂ represents from 0 to 3 substituents independently chosen from    R_(x), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and    di-(C₁-C₄alkyl)amino(C₁-C₄alkoxy) and YZ; or two adjacent R₁₂ groups    are joined to form a fused 5- to 7-membered carbocyclic or    heterocyclic ring.-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x);    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₂cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; or    -   (iii) two R₁₃ residues, taken in combination, form a fused        benzene ring which is substituted with from 0 to 4 substituents        independently chosen from halogen, hydroxy, COOH, CONH₂, SO₂NH₂,        amino, cyano, C₁-C₁alkyl, C₁-C₄alkoxy,        (C₃-C₂cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,        and mono- and di-(C₁-C₄alkyl)amino;-   G is CH₂, NH or oxygen; and-   x is 0, 1 or 2.

Other compounds of Formula VI and Formula VII include those in which R₁₂and R₁₃ independently represent from 0 to 2 substituents independentlychosen from halogen, methyl, methoxy and ethyl. Certain other compoundsof Formula VI and Formula VII include those in which R₇ is absent. Yetother compounds of Formula VI and Formula VII include those in which xis 1. Still other compounds of Formula VI and Formula VII include thosein which G is CH₂.

Other compounds of Formula VII include those in which R₅ is C₁-C₆alkyl;and R₁₂ and R₁₃ each represent from 0 to 2 substituents independentlychosen from halogen, methyl, methoxy and ethyl.

Other compounds of Formula II provided herein include those, which areherein defined as compounds of Formula II-b, in which:

-   A is OR₄; and-   R₄ is C₂-C₆alkyl, C₂-C₆alkenyl, phenylC₀-C₄alkyl,    naphthylC₀-C₄alkyl, pyridylC₀-C₄alkyl, thienylC₀-C₄alkyl,    imidazolylC₀-C₄alkyl or pyrrolylC₀-C₄alkyl, each of which is    substituted with from 0 to 4 substituents independently chosen from    R_(x), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and    di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered    heterocycloalkyl)C₀-C₄alkyl and C₂-C₄alkanoyl.

Certain compounds of Formula II-b include those in which R₄ is phenyl,benzyl, pyridyl or pyridylmethyl, each of which is substituted with from0 to 4 substituents independently chosen from R_(x), mono- anddi-C₁-C₄alkylamino(C₀-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl and C₂-C₄alkanoyl. Other compounds ofFormula II-b include those in which R₄ is (C₄₋₇cycloalkyl)C₀₋₄alkyl or(benzoC₃₋₇cycloalkyl)C₀₋₄alkyl, each of which is substituted with from 0to 4 substituents independently chosen from R_(x), mono- anddi-C₁-C₄alkylamino(C₀-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl and C₂-C₄alkanoyl.

Certain other compounds of Formula II-b include those in which

-   R₁ is chosen from hydrogen, halogen, amino, cyano, C₁-C₆alkyl,    C₃-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl,    C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, and    (C₃-C₇cycloalkyl)C₀-C₄alkyl;-   R₃ is selected from halogen, hydroxy, amino, cyano, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy,    C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆hydroxyalkyl, mono- and    di-(C₁₋₆alkyl)amino, C₁₋₆-aminoalkyl, C₃₋₇cycloalkyloxy; or-   R₁ and R₃, taken in combination form an optionally substituted fused    carbocyclic ring;-   R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy,    C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and    C₁-C₆alkoxy; and-   Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl, pyridyl,    pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,    imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl,    indolyl, indazolyl, and triazolyl, each of which is optionally    mono-, di-, or tri-substituted.

Still other compounds of Formula II-b include those in which R₁ and R₃,taken in combination, form a fused benzene ring.

Certain compounds of any one of Formula II, II-a, II-b, III, IV, V, VI,VII, or VIII include those compounds in which the Ar substituent isortho-substituted phenyl, optionally substituted naphthyl, or optionallysubstituted heteroaryl. In other compounds of any one of Formula II,II-a, II-b, III, IV, V, VI, VII, or VIII, Ar is selected from the groupconsisting of ortho-substituted phenyl which is optionally mono-, di-,or tri-substituted, or Ar is 1-naphthyl, 2-naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl,pyrrolyl, furanyl, and triazolyl, each of which is optionally mono-,di-, or tri-substituted

Certain other compounds of any one of Formula II, II-a, II-b, III, IV,V, VI, VII, or VIII include those compounds in which the Ar substituentis ortho-substituted phenyl substituted with between 1 and 3 residuesindependently selected from the group consisting of optionallysubstituted C₁₋₆alkyl, optionally substituted C₂₋₆alkenyl, optionallysubstituted C₂₋₆alkynyl, optionally substituted C₁₋₆alkoxy, optionallysubstituted (C₁₋₆alkoxy)C₁₋₆alkyl, optionally substituted(amino)C₁₋₆alkyl, optionally substituted mono- and di-(C₁₋₆alkyl)amino.

Certain compounds of Formula II, II-a, or II-b include those in which R₁is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl. In othercompounds of Formula II, II-a, or II-b, R₁ is hydrogen, C₁-C₄alkyl orC₁-C₄alkoxy, or more preferably R₁ is hydrogen, methyl, ethyl, ormethoxy.

Yet other compounds of Formula II, II-a, or II-b, include those in whichR₃ represents between 0 and 2 substituents, each of which isindependently selected from C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₆haloalkyl,C₁₋₆haloalkoxy, hydroxy, COOH, CONH₂, SO₂NH₂, mono- anddi-(C₁₋₆alkyl)amino, (amino)C₀₋₆alkyl. In certain other compounds ofFormula II, II-a, or II-b, R₃ represents between 0 and 2 substituents,each of which is independently selected from C₃₋₆alkyl, C₁₋₆alkoxy,hydroxy, COOH, CONH₂, and SO₂NH₂.

In yet other compounds of Formula II, II-a, or II-b, R₁ and R₃ taken incombination form an optionally substituted benzo ring. In certain othercompounds of Formula II, II-a, or II-b, R₁ and R₃ taken in combinationform a benzo ring substituted with between 0 and 2, 3, or 4 R₇substituents which are independently selected from the group consistingof C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, COOH, CONH₂,SO₂NH₂, hydroxy, halogen, and amino. Certain compounds of Formula Iinclude those in which A is NR₄R₅ and Ar is a heteroaryl group, whichcompounds are referred to herein as compounds of Formula I-a. Certaincompounds of Formula I-a include those in which R₁ is chosen fromhydrogen, halogen, amino, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, mono- anddi-(C₁-C₆alkyl)amino, and (C₃-C₂cycloalkyl)C₀-C₄alkyl; R₃ is selectedfrom halogen, hydroxy, amino, cyano, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl,C₁₋₆hydroxyalkyl, mono- and di-(C₁₋₆alkyl)amino, C₁₋₆-aminoalkyl,C₃₋₄cycloalkyloxy; or R₁ and R₃, taken in combination form an optionallysubstituted fused carbocyclic ring. In yet other compounds of FormulaI-1, R₁ and R₃, taken in combination, form a fused benzene ring.

In other compounds of Formula I-1, Ar is pyridyl, pyrimidinyl,pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl,tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl,or triazolyl, each of which is optionally mono-, di-, ortri-substituted. Typically when Ar is pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl,oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, ortriazolyl, each group is optionally substituted with between 1 and 3residues independently selected from the group consisting of optionallysubstituted C₁₋₆alkyl, optionally substituted C₂₋₆alkenyl, optionallysubstituted C₂₋₆alkynyl, optionally substituted C₁₋₆alkoxy, optionallysubstituted (C₁₋₆alkoxy)C₁₋₆alkyl, optionally substituted(amino)C₁₋₆alkyl, optionally substituted mono- and di-(C₁₋₆alkyl)amino.

In yet other compounds of Formula I-a R₄ is selected from the groupconsisting of

(i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl,pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl,pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl, benzoisothiazolyl ortetrahydronapthyl, each of which is substituted with from 0 to 4substituents independently chosen from R_(x), C₂-C₄alkanoyl, mono- anddi-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl and XR_(y); or

(ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅ arebound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members ineach ring, wherein the heterocycle is substituted with from 0 to 4substituents independently chosen from R_(x), oxo and W—Z; and

R₅ is:

(i) hydrogen;

(ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,(C₃-C₇-carbocycle)C₀-C₄alkyl, each of which is substituted with from 0to 3 substituents independently chosen from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino,trifluoromethyl and trifluoromethoxy; or

(iii) joined to R₄ to form an optionally substituted heterocycle.

Certain other compounds of Formula I-a include those in which R₄ ischosen from (C₃-C₂cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl,pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl,imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl,indolylC₀-C₄alkyl, indazolylC₀-C₄alkyl, benzocycloalkenylC₀-C₄alkyl,decahydronaphthylC₀-C₄alkyl, benzoisothiazolylC₀-C₄alkyl,tetrahydroquinolinylC₀-C₄alkyl and tetrahydronaphthylC₀-C₄alkyl, each ofwhich is substituted with from 0 to 4 groups independently chosen fromR_(x), mono- and di-C₁-C₄alkylamino(C₁-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl, C₂-C₄alkanoyl and C₂-C₄alkanoyloxy; and R₅is C₁-C₆alkyl, C₂-C₆alkenyl or (C₃-C₂-carbocycle)C₀-C₄alkyl.

Yet other compounds of Formula I-a include those in which R₄ and R₅ arejoined to form a saturated or partially saturated heterocycle containing1 or 2 fused or spiro rings; wherein the heterocycle is substituted withfrom 0 to 4 substituents independently chosen from halogen, hydroxy,amino, cyano, —COOH, —CH₂COOH, C₁₋₆alkoxycarbonyl, —CH₂CO₂—C₁₋₆alkyl,—C(O)NH₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- anddi-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, —S(O_(n))C₁-C₆alkyl, SO₃H, and phenyl. Incertain compounds of Formula I-1, R₄ and R₅ are joined to form asaturated 4- to 7-membered heterocyclic ring that is substituted withfrom 0 to 3 substituents independently chosen from halogen, hydroxy,amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, difluoromethyl,trifluoromethoxy difluoromethoxy, —COOH, —CH₂COOH, C₁₋₂alkoxycarbonyl,and —CH₂CO₂—C₁₋₂alkyl. Typically heterocyclic rings include azepanyl,morpholinyl, homomorpholinyl, pyrrolidinyl, piperazinyl,homopiperazinyl, piperidinyl, or homopiperidinyl.

Certain compounds of Formula I include those in which A is NR₅R₆, whichcompounds are referred to herein as compounds of Formula I-b.

In certain compounds of Formula I-b, ortho-substituted phenyl,1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl,thienyl, triazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl,isoxazolyl, pyrrolyl, furanyl, indolyl, indazolyl, and triazolyl, eachof which is optionally mono-, di-, or tri-substituted. In yet othercompounds of Formula I-b, Ar is or/ho-substituted phenyl substitutedhaving 1 and 3 residues independently selected from the group consistingof optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆alkenyl,optionally substituted C₂₋₆alkynyl, optionally substituted C₁₋₆alkoxy,optionally substituted (C₁₋₆alkoxy)C₁₋₆alkyl, optionally substituted(amino)C₁₋₆alkyl, optionally substituted mono- and di-(C₁₋₆alkyl)amino.

Other compounds of Formula I-b include those in which

-   R₆ is benzyl, C₄-C₁₀-carbocycle, (C₄-C₁₀carbocycle)methyl,    benzoC₅-C₇-carbocycle, (benzoC₅-C₇-carbocycle)methyl,    benzoC₅-C₇heterocycle, (benzoC₅-C₇heterocycle)methyl, each of which    is substituted with from 0 to 3 substituents independently chosen    from halogen, hydroxy, amino, cyano, C₁-C₄alkoxy, methylamino,    dimethylamino, trifluoromethyl, phenoxy substituted with between 0-2    R_(x) groups, C₁₋₂alkylenedioxy, and trifluoromethoxy; and-   R_(x) is independently selected at each occurrence from the group    consisting of halogen, hydroxy, amino, cyano, nitro, —COOH,    —C(═O)NH₂, SO₂NH₂, C₁-C₆alkoxycarbonyl, mono- and    di-(C₁₋₆alkyl)aminocarbonyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl,    C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and    —S(O_(n))C₁-C₆alkyl.

Yet other compounds of Formula I-b include those in which R₆ is benzyl,tetrahydronapthylenyl, C₄₋₇cycloalkyl, C₄₋₇cycloalkyl,C₄₋₇cycloalkylmethyl, indanyl, and tetrahydrobenzocycloheptenyl, each ofwhich is substituted with between 0-2 R_(x) groups; and R_(x) isindependently selected at each occurrence from the group consisting ofhalogen, hydroxy, amino, cyano, nitro, —COOH, —C(O)NH₂, SO₂NH₂,C₁-C₆alkoxycarbonyl, —C(═O)NHC₁-C₆alkyl, —C(═O)N(C₁-C₆alkyl)₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino,C₁-C₆alkoxy, C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, and — S(O_(n))C₁-C₆alkyl.

Certain other compounds of Formula I-b include those in which R₁ ischosen from hydrogen, halogen, amino, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, mono- anddi-(C₁-C₆alkyl)amino, and (C₃-C₇cycloalkyl)C₀-C₄alkyl; R₃ is selectedfrom halogen, hydroxy, amino, cyano, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl,C₁₋₆hydroxyalkyl, mono- and di-(C₁₋₆alkyl)amino, C₁₋₆aminoalkyl,C₃₋₇cycloalkyloxy; or R₁ and R₃, taken in combination form an optionallysubstituted fused carbocyclic ring.

In yet other compounds of Formula I-b, R₁ and R₃, taken in combination,form a fused benzene ring. In certain compounds of Formula I-b, R₁ andR₃, taken in combination form an fused benzo ring substituted withbetween 0-2 R_(x) groups; and R_(x) is independently selected at eachoccurrence from the group consisting of halogen, hydroxy, amino, cyano,nitro, —COOH, —C(═O)NH₂, SO₂NH₂, C₁-C₆alkoxycarbonyl, -mono- anddi-(C₁₋₆alkyl)aminocarbonyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and—S(O_(n))C₁-C₆alkyl.

Certain compounds of Formula I-b include those in which R₅ and R₆ arejoined to form a saturated 4- to 7-membered heterocyclic ring that issubstituted with from 0 to 3 substituents independently chosen fromhalogen, hydroxy, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy,trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy,—COOH, —CH₂COOH, —CO₂—C₁₋₂alkyl, phenoxy or phenyl substituted with 0-3R_(x) groups, and —CH₂CO₂—C₁₋₂alkyl. Typically heterocyclic rings areselected from azepanyl, morpholinyl, homomorpholinyl, pyrrolidinyl,piperazinyl, homopiperazinyl, piperidinyl, or homopiperidinyl.

Still other compounds of Formula I-B include those having a formula:

wherein:

Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl,indolyl, indazolyl, and triazolyl, each of which is optionally mono-,di-, or tri-substituted;

-   R₁ is chosen from hydrogen, halogen, amino, cyano, C₁-C₆alkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl,    C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, and    (C₃-C₇cycloalkyl)C₀-C₄alkyl;-   R₃ is selected from halogen, hydroxy, amino, cyano, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy,    C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆hydroxyalkyl, mono- and    di-(C₁₋₆alkyl)amino, C₁₋₆aminoalkyl, C₃₋₇cycloalkyloxy; or-   R₁ and R₃, taken in combination form an optionally substituted fused    carbocyclic ring.-   R₅ is:    -   (i) hydrogen;    -   (ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        (C₇-C₇-carbocycle)C₀-C₄alkyl, each of which is substituted with        from 0 to 3 substituents independently chosen from halogen,        hydroxy, amino, cyano, C₁-C₄alkoxy, methylamino, dimethylamino,        trifluoromethyl and trifluoromethoxy;-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x);    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; or    -   (iii) two R₁₃ residues, taken in combination, form a fused        benzene ring which is substituted with from 0 to 4 substituents        independently chosen from halogen, hydroxy, COOH, CONH₂, SO₂NH₂,        amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,        and mono- and di-(C₁-C₄alkyl)amino;-   G is CH₂, CHR₁₃, sulfur, oxygen or NR_(E); wherein R_(E) is:    -   (i) hydrogen; or    -   (ii) C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenyl or a 5- or        6-membered heteroaryl ring, each of which is substituted with        from 0 to 3 substituents independently chosen from R_(x);-   R_(x) is independently chosen at each occurrence from halogen,    hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH₂, C₁-C₆alkoxycarbonyl,    mono- and di-(C₁₋₆alkyl)aminocarbonyl, C₁-C₆alkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy,    C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,    (C₃-C₇cycloalkyl)C₀-C₄alkyl, and —S(O_(n))C₁-C₆alkyl; and-   x is 0, 1, 2, or 3.

Yet other compounds of Formula I-B include those having a formula:

wherein:

Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl,indolyl, indazolyl, and triazolyl, each of which is optionally mono-,di-, or tri-substituted;

-   R₁ is chosen from hydrogen, halogen, amino, cyano, C₁-C₆alkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl,    C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, and    (C₃-C₇cycloalkyl)C₀-C₄alkyl;-   R₃ is selected from halogen, hydroxy, amino, cyano, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy,    C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆hydroxyalkyl, mono- and    di-(C₁₋₆alkyl)amino, C₁₋₆aminoalkyl, C₃₋₇cycloalkyloxy; or-   R₁ and R₃, taken in combination form an optionally substituted fused    carbocyclic ring.-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x);    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; or    -   (iii) two R₁₃ residues, taken in combination, form a fused        benzene ring which is substituted with from 0 to 4 substituents        independently chosen from halogen, hydroxy, COOH, CONH₂, SO₂NH₂,        amino, cyano, C₁-C₄alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl,        C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and mono- and        di-(C₁-C₄alkyl)amino;-   G is CH₇, CHR₁₃, sulfur, oxygen or NR_(E); wherein R_(E) is:    -   (i) hydrogen; or    -   (ii) (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenyl or a 5- or 6-membered        heteroaryl ring, each of which is substituted with from 0 to 3        substituents independently chosen from R_(x);-   R_(x) is independently chosen at each occurrence from halogen,    hydroxy, amino, cyano, nitro, —COOH, — C(═O)NH₂,    C₁-C₆alkoxycarbonyl, mono- and di-(C₁₋₆alkyl)aminocarbonyl,    C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and    di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl,    C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and    —S(O_(n))C₁-C₆alkyl; and-   x is 0, 1, 2, or 3.

Certain other compounds of Formula include those having a formula:

wherein:

Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl,indolyl, indazolyl, and triazolyl, each of which is optionally mono-,di-, or tri-substituted;

-   R₁ is chosen from hydrogen, halogen, amino, cyano, C₁-C₆alkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl,    C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, and    (C₃-C₇cycloalkyl)C₀-C₄alkyl;-   R₃ is selected from halogen, hydroxy, amino, cyano, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy,    C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆ hydroxyalkyl, mono- and    di-(C₁₋₆alkyl)amino, C₁₋₆aminoalkyl, C₃₋₇cycloalkyloxy; or-   R₁ and R₃, taken in combination form an optionally substituted fused    carbocyclic ring.-   R₁₂ represents from 0 to 3 substituents independently chosen from    R_(x), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and    di-(C₁-C₄alkyl)amino(C₁-C₄alkoxy) and YZ; or two adjacent R₁₂ groups    are joined to form a fused 5- to 7-membered carbocyclic or    heterocyclic ring.-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x);    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; or    -   (iii) two R₁₃ residues, taken in combination, form a fused        benzene ring which is substituted with from 0 to 4 substituents        independently chosen from halogen, hydroxy, COOH, CONH₂, SO₂NH₂,        amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,        and mono- and di-(C₁-C₄alkyl)amino;-   G is CH₂, CHR₁₃, sulfur, oxygen or NR_(E); wherein R_(E) is:    -   (i) hydrogen; or    -   (ii) C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenyl or a 5- or        6-membered heteroaryl ring, each of which is substituted with        from 0 to 3 substituents independently chosen from R_(x);-   R_(x) is independently chosen at each occurrence from halogen,    hydroxy, amino, cyano, nitro, —COOH, — C(═O)NH₂,    C₁-C₆alkoxycarbonyl, mono- and di-(C₁₋₆alkyl)aminocarbonyl,    C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and    di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl,    C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and    —S(O_(n))C₁-C₆alkyl; and-   x is 1, 2, or 3.

Yet other compounds of Formula I-B include those having a formula:

wherein:

Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl,indolyl, indazolyl, and triazolyl, each of which is optionally mono-,di-, or tri-substituted;

-   R₁ is chosen from hydrogen, halogen, amino, cyano, C₁-C₆alkyl,    C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl,    C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, and    (C₇-C₇cycloalkyl)C₀-C₄alkyl;-   R₃ is selected from halogen, hydroxy, amino, cyano, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₄alkoxy,    C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆hydroxyalkyl, mono- and    di-(C₁₋₆alkyl)amino, C₁₋₆aminoalkyl, C₃₋₇cycloalkyloxy; or-   R₁ and R₃, taken in combination form an optionally substituted fused    carbocyclic ring.-   R₁₂ represents from 0 to 3 substituents independently chosen from    R_(x), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and    di-(C₁-C₄alkyl)amino(C₁-C₄alkoxy) and YZ; or two adjacent R₁₂ groups    are joined to form a fused 5- to 7-membered carbocyclic or    heterocyclic ring.-   R₁₃ represents from 0 to 3 substituents independently chosen from:    -   (i) R_(x);    -   (ii) phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is        substituted with from 0 to 4 substituents independently chosen        from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and        mono- and di-(C₁-C₄alkyl)amino; or    -   (iii) two R₁₃ residues, taken in combination, form a fused        benzene ring which is substituted with from 0 to 4 substituents        independently chosen from halogen, hydroxy, COOH, CONH₂, SO₂NH₂,        amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,        (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,        and mono- and di-(C₁-C₄alkyl)amino;-   R₁₄ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,    C₁-C₂haloalkyl or (C₃-C₇cycloalkyl)C₀-C₂alkyl, COOH, CONH₂, CH₂COOH,    CH₂CONH₂, CO₂—C₁₋₆alkyl, CH₂CO₂—C₁₋₆alkyl, or SO₃H;-   R_(x) is independently chosen at each occurrence from halogen,    hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH₂, C₁-C₆alkoxycarbonyl,    mono- and di-(C₁₋₆alkyl)aminocarbonyl, C₁-C₆alkyl, C₂-C₆alkenyl,    C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy,    C₁-C₂hydroxyalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and    —S(O_(n))C₁-C₆alkyl; and-   x is 1, 2, or 3.

Certain compounds of Formula VIII, IX, X, and XI include those in whichR₁ and R₃, taken in combination form a fused benzene ring which issubstituted with between 0-2 groups independently selected from halogen,hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH₂, C₁-C₆alkoxycarbonyl,—C(═O)NHC₁-C₆alkyl, —C(═O)N(C₁-C₆alkyl)₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy,C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, and —S(O_(n))C₁-C₆alkyl.

In certain compounds of Formula I, II, IX and the other Formulasdescribed above, “optionally substituted” residues are substituted withfrom 0 to 4 substituents independently selected from oxo, hydroxy,halogen, cyano, amino, nitro, —COOH, aminocarbonyl, —SO₂NH₂, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆aminoalkyl,C₁₋₆hydroxyalkyl, C₁₋₆-carboxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkylthio, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₃₋₆alkanone, C₁₋₆alkylether, mono- or di-(C₁₋₆alkyl)aminoC₀₋₆alkyl, —NHC(═O)(C₁₋₆alkyl),—N(C₁₋₆alkyl)C(═O)(C₁₋₆alkyl), —NH S(O)_(n)(C₁₋₆alkyl),—(C₁₋₆alkyl)C(═O)NH₂, —(C₁₋₆alkyl)C(═O)NH(C₁₋₆alkyl),—(C₁₋₆alkyl)C(═O)NH(C₁₋₆alkyl)(C₁₋₆alkyl), —S(O)_(n)(C₁₋₆alkyl),—S(O)_(n)NH(C₁₋₆alkyl), —S(O)_(n)N(C₁₋₆alkyl)(C₁₋₆alkyl) and Z, in whichn and Z are as described above. In other compounds of Formula I and theother Formulas described above, “optionally substituted” residues aresubstituted with from 0 to 4 substituents independently selected fromhydroxy, halogen, cyano, amino, —COOH, aminocarbonyl, —SO₂NH₂,C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, and mono- ordi-(C₁₋₄alkyl)aminoC₀₋₄alkyl. Similarly, in certain compounds, “mono-,di- or tri-substituted” residues are substituted with 1, 2 or 3substituents independently chosen from the groups indicated above.

Certain compounds according to the Formulas provided herein, which havetwo or more stereogenic centers, have a diastereomeric excess of atleast 50%. For example, such compounds may have a diastereomeric excessof at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Certain such compoundshave a diastereomeric excess of at least 99%.

Certain compounds according to the Formulas provided herein, which haveone or more stereogenic center, have an enantiomeric excess of at least50%. For example, such compounds may have an enantiomeric excess of atleast 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Certain such compounds havean enantiomeric excess of at least 99%. It will be apparent that singleenantiomers (optically active forms) can be obtained by asymmetricsynthesis, synthesis from optically pure precursors or by resolution ofthe racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralHPLC column

3-Aryl-5,6-disubstituted pyridazines and pharmaceutically acceptablesalts thereof provided herein detectably alter (modulate) C5a receptoractivity and/or ligand binding, as determined using a standard in vitroC5 receptor-mediated chemotaxis assay (described in Example 6),radioligand binding (described in Example l 4), or C5a receptor-mediatedcalcium mobilization assay (described in Example 16). Certain compoundsexhibit an EC₅₀ of about 500 nM or less in such a standard C5areceptor-mediated chemotaxis, radioligand binding, and/or calciummobilization assay, more preferably an EC₅₀ of about 250 nM or less insuch an assay, still more preferably an EC₅₀ of about 200, 150, 100, 50,25, 10, or 5 nM or less in such an assay.

Initial characterization of compounds can be conveniently carried outusing a C5a receptor binding assay or functional assay, such as setforth in the Examples, and may be expedited by applying such assays in ahigh throughput screening setting. Additional assays suitable fordetermining the effects of small molecule compounds on C5a receptorbinding and receptor modulatory activity, as well as assays suitable formeasuring their effects on C5a-induced neutropenia in vivo, can be foundin the published literature, for example in U.S. Pat. No. 5,807,824,which is incorporated herein by reference for its disclosure in thisregard in Examples 6-9, columns 19-23, as well as for its discussion ofcomplement and inflammation at columns 1-2. Those of skill in the artwill recognize that such assays can be readily adapted to the use ofcells or animals of different species as deemed appropriate.

In certain embodiments, preferred compounds have favorablepharmacological properties, including oral bioavailability (such that asub-lethal or preferably a pharmaceutically acceptable oral dose,preferably less than 2 grams, more preferably of less than or equal toone gram, can provide a detectable in vivo effect such as a reduction ofC5a-induced neutropenia), ability to inhibit leukocyte chemotaxis atnanomolar concentrations and preferably at sub-nanomolar concentrations,low toxicity (a preferred compound is nontoxic when a therapeuticallyeffective amount is administered to a subject), minimal side effects (apreferred compound produces side effects comparable to placebo when atherapeutically effective amount of the compound is administered to asubject), low serum protein binding, and a suitable in vitro and in vivohalf-life (a preferred compound exhibits an in vitro half-life that isequal to an in vivo half-life allowing for Q.I.D. dosing, preferablyT.I.D. dosing, more preferably B.I.D. dosing, and most preferablyonce-a-day dosing). Distribution in the body to sites of complementactivity is also desirable (e.g., compounds used to treat CNS disorderswill preferably penetrate the blood brain barrier, while low brainlevels of compounds used to treat periphereal disorders are typicallypreferred).

Routine assays that are well known in the art may be used to assessthese properties, and identify superior compounds for a particular use.For example, assays used to predict bioavailability include transportacross human intestinal cell monolayers, such as Caco-2 cell monolayers,Penetration of the blood brain barrier of a compound in humans may bepredicted from the brain levels of the compound in laboratory animalsgiven the compound (e.g., intravenously). Serum protein binding may bepredicted from albumin binding assays, such as those described byOravcová, et al. (1996) Journal of Chromatography B 677:1-27. Compoundhalf-life is inversely proportional to the frequency of dosage of acompound required to achieve an therapeutically effective amount. Invitro half-lives of compounds may be predicted from assays of microsomalhalf-life as described by Kuhnz and Gieschen (1998) Drug Metabolism andDisposition 26:1120-27.

As noted above, preferred compounds provided herein are nontoxic. Ingeneral, the term “nontoxic” as used herein shall be understood in arelative sense and is intended to refer to any substance that has beenapproved by the United States Food and Drug Administration (“FDA”) foradministration to mammals (preferably humans) or, in keeping withestablished criteria, is susceptible to approval by the FDA foradministration to mammals (preferably humans). In addition, a highlypreferred nontoxic compound generally satisfies one or more of thefollowing criteria: (1) does not substantially inhibit cellular ATPproduction; (2) does not significantly prolong heart QT intervals; (3)does not cause substantial liver enlargement, and (4) does not causesubstantial release of liver enzymes.

As used herein, a compound that “does not substantially inhibit cellularATP production” is a compound that satisfies the criteria set forth inExample 18, herein. In other words, cells treated as described inExample 18 with 100 μM of such a compound exhibit ATP levels that are atleast 50% of the ATP levels detected in untreated cells. In more highlypreferred embodiments, such cells exhibit ATP levels that are at least80% of the ATP levels detected in untreated cells.

A compound that “does not significantly prolong heart QT intervals” is acompound that does not result in a statistically significantprolongation of heart QT intervals (as determined byelectrocardiography) in guinea pigs, minipigs or dogs uponadministration of twice the minimum dose yielding a therapeuticallyeffective in vivo concentration. In certain preferred embodiments, adose of 0.01, 0.05. 0.1, 0.5, 1, 5, 10, 40 or 50 mg/kg administeredparenterally or orally does not result in a statistically significantprolongation of heart QT intervals. By “statistically significant” ismeant results varying from control at the p<0.1 level or more preferablyat the p<0.05 level of significance as measured using a standardparametric assay of statistical significance such as a student's T test.

A compound “does not cause substantial liver enlargement” if dailytreatment of laboratory rodents (e.g., mice or rats) for 5-10 days withtwice the minimum dose that yields a therapeutically effective in vivoconcentration results in an increase in liver to body weight ratio thatis no more than 100% over matched controls. In more highly preferredembodiments, such doses do not cause liver enlargement of more than 75%or 50% over matched controls. If non-rodent mammals (e.g., dogs) areused, such doses should not result in an increase of liver to bodyweight ratio of more than 50%, preferably not more than 25%, and morepreferably not more than 10% over matched untreated controls. Preferreddoses within such assays include 0.01, 0.05. 0.1, 0.5, 1, 5, 10, 40 or50 mg/kg administered parenterally or orally.

Similarly, a compound “does not promote substantial release of liverenzymes” if administration of twice the minimum dose yielding atherapeutically effective in vivo concentration does not elevate serumlevels of ALT, LDH or AST in laboratory rodents by more than 100% overmatched mock-treated controls. In more highly preferred embodiments,such doses do not elevate such serum levels by more than 75% or 50% overmatched controls. Alternately, a compound “does not promote substantialrelease of liver enzymes” if, in an in vitro hepatocyte assay,concentrations (in culture media or other such solutions that arecontacted and incubated with hepatocytes in vitro) equivalent totwo-fold the minimum in vivo therapeutic concentration of the compounddo not cause detectable release of any of such liver enzymes intoculture medium above baseline levels seen in media from matchedmock-treated control cells. In more highly preferred embodiments, thereis no detectable release of any of such liver enzymes into culturemedium above baseline levels when such compound concentrations arefive-fold, and preferably ten-fold the minimum in vivo therapeuticconcentration of the compound.

In other embodiments, certain preferred compounds do not inhibit orinduce microsomal cytochrome P450 enzyme activities, such as CYP1A2activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6activity, CYP2E1 activity or CYP3A4 activity at a concentration equal tothe minimum therapeutically effective in vivo concentration.

Certain preferred compounds are not clastogenic or mutagenic (e.g., asdetermined using standard assays such as the Chinese hamster ovary cellvitro micronucleus assay, the mouse lymphoma assay, the human lymphocytechromosomal aberration assay, the rodent bone marrow micronucleus assay,the Ames test or the like) at a concentration equal to the minimumtherapeutically effective in vivo concentration. In other embodiments,certain preferred compounds do not induce sister chromatid exchange(e.g., in Chinese hamster ovary cells) at such concentrations.

In certain embodiments, preferred compounds exert theirreceptor-modulatory effects with high specificity. This means that theyonly bind to, activate, or inhibit the activity of certain receptorsother than C5a receptors with affinity constants of greater than 100nanomolar, preferably greater than 1 micromolar, more preferably greaterthan 4 micromolar. Also provided herein are highly specifictherapeutically effective compounds that exhibit 200-fold greateraffinity for C5a receptor that for other cellular receptors. Suchreceptors include neurotransmitter receptors such as alpha- orbeta-adrenergic receptors, muscarinic receptors (particularly m1, m2 orm3 receptors), dopamine receptors, and metabotropic glutamate receptors;as well as histamine receptors and cytokine receptors (e.g., interleukinreceptors, particularly IL-8 receptors). Such receptors may also includeGABA_(A) receptors, bioactive peptide receptors (other than C5areceptors and C3a receptors, including NPY or VIP receptors), neurokininreceptors, bradykinin receptors, and hormone receptors (e.g., CRFreceptors, thyrotropin releasing hormone receptors ormelanin-concentrating hormone receptors). Compounds that act with highspecificity generally exhibit fewer undesirable side effects.

Within certain embodiments, modulators provided herein do not binddetectably to receptors that do not mediate inflammatory responses, suchas GABA receptors, MCH receptors, NPY receptors, dopamine receptors,serotonin receptors and VR1 receptors, with high or even moderateaffinity. In addition, or alternatively, certain preferred C5a receptormodulators exhibit an affinity for C5a receptor that is substantiallyhigher than for receptors that do not mediate inflammatory responses(e.g., at least five times higher, at least ten times higher or at least100 times higher). Assays for evaluating binding to receptors that donot mediate inflammatory responses include, for example, those describedin U.S. Pat. No. 6,310,212, which is incorporated herein by referencefor its disclosure of a GABA_(A) receptor binding assays in Examples 14,columns 16-17, in U.S. patent application Ser. No. 10/152,189 which isincorporated herein by reference for its disclosure of an MCH receptorbinding assay in Example 2, pages 104-105, in U.S. Pat. No. 6,362,186,which is incorporated herein by reference for its disclosure of CRF₁ andNPY receptor binding assays in Example 19, columns 45-46, in U.S. Pat.No. 6,355,644, which is incorporated herein by reference for itsdisclosure of a dopamine receptor binding assay at column 10, and inU.S. Pat. No. 6,482,611, which is incorporated herein by reference forits disclosure of VR1 receptor binding assays in Examples 4-5, column14. It will be apparent that C5a receptor modulators provided hereinmay, but need not, bind to one or more other receptors known to mediateinflammatory responses, such as C3a receptors and/or A₃ receptors.

Certain preferred compounds are C5a receptor antagonists that do notpossess significant (e.g., greater than 5%) agonist activity in any ofC5a receptor-mediated functional assays discussed herein. Specifically,this undesired agonist activity can be evaluated, for example, in theGTP binding assay of Example 15, by measuring small molecule mediatedGTP binding in the absence of the natural agonist, C5a. Similarly, in acalcium mobilization assay (e.g., that of Example 16) a small moleculecompound can be directly assayed for the ability of the compound tostimulate calcium levels in the absence of the natural agonist, C5a. Thepreferred extent of C5a agonist activity exhibited by compounds providedherein is less than 10%, 5% or 2% of the response elicited by thenatural agonist, C5a.

Also preferred, in certain embodiments, are C5a receptor modulators thatinhibit the occurrence of C5a-induced oxidative burst (OB) ininflammatory cells (e.g., neutrophil) as can be conveniently determinedusing an in vitro neutrophil OB assay.

For detection purposes, compounds provided herein may beisotopically-labeled or radiolabeled. Accordingly, compounds recited inFormula I (or any other formula specifically recited herein) may haveone or more atoms replaced by an atom of the same element having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be present incompounds provided herein include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. In addition,substitution with heavy isotopes such as deuterium (i.e., ²H) can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositionscomprising one or more C5a receptor modulators provided herein, togetherwith at least one physiologically acceptable carrier or excipient.Pharmaceutical compositions may comprise, for example, one or more ofwater, buffers (e.g., neutral buffered saline or phosphate bufferedsaline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide,carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol,proteins, adjuvants, polypeptides or amino acids such as glycine,antioxidants, chelating agents such as EDTA or glutathione and/orpreservatives. As noted above, other active ingredients may (but neednot) be included in the pharmaceutical compositions provided herein.

Pharmaceutical compositions may be formulated for any appropriate mannerof administration, including, for example, topical (e.g., transdermal orocular), oral, nasal, rectal or parenteral administration. The termparenteral as used herein includes subcutaneous, intradermal,intravascular (e.g., intravenous), intramuscular, spinal, intracranial,intrathecal and intraperitoneal injection, as well as any similarinjection or infusion technique. In certain embodiments, compositions ina form suitable for oral use are preferred. Such forms include, forexample, tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs. Within yet other embodiments, compositions providedherein may be formulated as a lyophilizate. Formulation for topicaladministration may be preferred for certain conditions (e.g., in thetreatment of skin conditions such as burns or itch).

Compositions intended for oral use may further comprise one or morecomponents such as sweetening agents, flavoring agents, coloring agentsand/or preserving agents in order to provide appealing and palatablepreparations. Tablets contain the active ingredient in admixture withphysiologically acceptable excipients that are suitable for themanufacture of tablets. Such excipients include, for example, inertdiluents (e.g., calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate), granulating and disintegrating agents(e.g., corn starch or alginic acid), binding agents (e.g., starch,gelatin or acacia) and lubricating agents (e.g., magnesium stearate,stearic acid or talc). The tablets may be uncoated or they may be coatedby known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent(e.g., calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium (e.g., peanut oil, liquid paraffin or olive oil).

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents (e.g., sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia);and dispersing or wetting agents (e.g., naturally-occurring phosphatidessuch as lecithin, condensation products of an alkylene oxide with fattyacids such as polyoxyethylene stearate, condensation products ofethylene oxide with long chain aliphatic alcohols such asheptadecaethyleneoxycetanol, condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides such as polyethylene sorbitan monooleate). Aqueoussuspensions may also comprise one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconutoil) or in a mineral oil such as liquid paraffin. The oily suspensionsmay contain a thickening agent such as beeswax, hard paraffin or cetylalcohol. Sweetening agents such as those set forth above, and/orflavoring agents may be added to provide palatable oral preparations.Such suspensions may be preserved by the addition of an anti-oxidantsuch as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, such as sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil (e.g., olive oil orarachis oil), a mineral oil (e.g., liquid paraffin) or a mixturethereof. Suitable emulsifying agents include naturally-occurring gums(e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides(e.g., soy bean lecithin, and esters or partial esters derived fromfatty acids and hexitol), anhydrides (e.g., sorbitan monoleate) andcondensation products of partial esters derived from fatty acids andhexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate).An emulsion may also comprise one or more sweetening and/or flavoringagents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso comprise one or more demulcents, preservatives, flavoring agentsand/or coloring agents.

Compounds may be formulated for local or topical administration, such asfor topical application to the skin or mucous membranes, such as theeye. Formulations for topical administration typically comprise atopical vehicle combined with active agent(s), with or withoutadditional optional components. Suitable topical vehicles and additionalcomponents are well known in the art, and it will be apparent that thechoice of a vehicle will depend on the particular physical form and modeof delivery. Topical vehicles include water; organic solvents such asalcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols(e.g.; butylene, isoprene or propylene glycol); aliphatic alcohols(e.g., lanolin); mixtures of water and organic solvents and mixtures oforganic solvents such as alcohol and glycerin; lipid-based materialssuch as fatty acids, acylglycerols (including oils, such as mineral oil,and fats of natural or synthetic origin), phosphoglycerides,sphingolipids and waxes; protein-based materials such as collagen andgelatin; silicone-based materials (both non-volatile and volatile); andhydrocarbon-based materials such as microsponges and polymer matrices. Acomposition may further include one or more components adapted toimprove the stability or effectiveness of the applied formulation, suchas stabilizing agents, suspending agents, emulsifying agents, viscosityadjusters, gelling agents, preservatives, antioxidants, skin penetrationenhancers, moisturizers and sustained release materials. Examples ofsuch components are described in Martindale—The Extra Pharmacopoeia(Pharmaceutical Press, London 1993) and Martin (ed.), Remington'sPharmaceutical Sciences. Formulations may comprise microcapsules, suchas hydroxymethylcellulose or gelatin-microcapsules, liposomes, albuminmicrospheres, microemulsions, nanoparticles or nanocapsules.

A topical formulation may be prepared in a variety of physical formsincluding, for example, solids, pastes, creams, foams, lotions, gels,powders, aqueous liquids, emulsions, sprays, and skin patches. Thephysical appearance and viscosity of such forms can be governed by thepresence and amount of emulsifier(s) and viscosity adjuster(s) presentin the formulation. Solids are generally firm and non-pourable andcommonly are formulated as bars or sticks, or in particulate form;solids can be opaque or transparent, and optionally can containsolvents, emulsifiers, moisturizers, emollients, fragrances,dyes/colorants, preservatives and other active ingredients that increaseor enhance the efficacy of the final product. Creams and lotions areoften similar to one another, differing mainly in their viscosity; bothlotions and creams may be opaque, translucent or clear and often containemulsifiers, solvents, and viscosity adjusting agents, as well asmoisturizers, emollients, fragrances, dyes/colorants, preservatives andother active ingredients that increase or enhance the efficacy of thefinal product. Gels can be prepared with a range of viscosities, fromthick or high viscosity to thin or low viscosity. These formulations,like those of lotions and creams, may also contain solvents,emulsifiers, moisturizers, emollients, fragrances, dyes/colorants,preservatives and other active ingredients that increase or enhance theefficacy of the final product. Liquids are thinner than creams, lotions,or gels and often do not contain emulsifiers. Liquid topical productsoften contain solvents, emulsifiers, moisturizers, emollients,fragrances, dyes/colorants, preservatives and other active ingredientsthat increase or enhance the efficacy of the final product.

Suitable emulsifiers for use in topical formulations include, but arenot limited to, ionic emulsifiers, cetearyl alcohol, non-ionicemulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate,ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100stearate and glyceryl stearate. Suitable viscosity adjusting agentsinclude, but are not limited to, protective colloids or non-ionic gumssuch as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate,silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. Agel composition may be formed by the addition of a gelling agent such aschitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol,polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.Suitable surfactants include, but are not limited to, nonionic,amphoteric, ionic and anionic surfactants. For example, one or more ofdimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleylbetaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammoniumlaureth sulfate may be used within topical formulations. Suitablepreservatives include, but are not limited to, antimicrobials such asmethylparaben, propylparaben, sorbic acid, benzoic acid, andformaldehyde, as well as physical stabilizers and antioxidants such asvitamin E, sodium ascorbate/ascorbic acid and propyl gallate. Suitablemoisturizers include, but are not limited to, lactic acid and otherhydroxy acids and their salts, glycerin, propylene glycol, and butyleneglycol. Suitable emollients include lanolin alcohol, lanolin, lanolinderivatives, cholesterol, petrolatum, isostearyl neopentanoate andmineral oils. Suitable fragrances and colors include, but are notlimited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitableadditional ingredients that may be included a topical formulationinclude, but are not limited to, abrasives, absorbents, anti-cakingagents, anti-foaming agents, anti-static agents, astringents (e.g.,witch hazel, alcohol and herbal extracts such as chamomile extract),binders/excipients, buffering agents, chelating agents, film formingagents, conditioning agents, propellants, opacifying agents, pHadjusters and protectants.

An example of a suitable topical vehicle for formulation of a gel is:hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol/water (90.9%);propylene glycol (5.1%); and Polysorbate 80 (1.9%). An example of asuitable topical vehicle for formulation as a foam is: cetyl alcohol(1.1%); stearyl alcohol (0.5%; Quaternium 52 (1.0%); propylene glycol(2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75hydrocarbon propellant (4.30%). All percents are by weight.

Typical modes of delivery for topical compositions include applicationusing the fingers; application using a physical applicator such as acloth, tissue, swab, stick or brush; spraying (including mist, aerosolor foam spraying); dropper application; sprinkling; soaking; andrinsing. Controlled release vehicles can also be used, and compositionsmay be formulated for transdermal administration as a transdermal patch

A pharmaceutical composition may be prepared as a sterile injectibleaqueous or oleaginous suspension. The modulator, depending on thevehicle and concentration used, can either be suspended or dissolved inthe vehicle. Such a composition may be formulated according to the knownart using suitable dispersing, wetting agents and/or suspending agentssuch as those mentioned above. Among the acceptable vehicles andsolvents that may be employed are water, 1,3-butanediol, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils may be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectible compositions, and adjuvants such as localanesthetics, preservatives and/or buffering agents can be dissolved inthe vehicle.

C5a modulators described herein may be formulated as inhaledformulations, including sprays, mists, or aerosols. Such formulationsare particularly useful for the treatment of asthma or other respiratoryconditions. For inhalation formulations, the compounds provided hereinmay be delivered via any inhalation methods known to those skilled inthe art. Such inhalation methods and devices include, but are notlimited to, metered dose inhalers with propellants such as CFC or HFA orpropellants that are physiologically and environmentally acceptable.Other suitable devices are breath operated inhalers, multidose drypowder inhalers and aerosol nebulizers. Aerosol formulations for use inthe subject method typically include propellants, surfactants andco-solvents and may be filled into conventional aerosol containers thatare closed by a suitable metering valve.

Inhalant compositions may comprise liquid or powdered compositionscontaining the active ingredient that are suitable for nebulization andintrabronchial use, or aerosol compositions administered via an aerosolunit dispensing metered doses. Suitable liquid compositions comprise theactive ingredient in an aqueous, pharmaceutically acceptable inhalantsolvent, e.g., isotonic saline or bacteriostatic water. The solutionsare administered by means of a pump or squeeze-actuated nebulized spraydispenser, or by any other conventional means for causing or enablingthe requisite dosage amount of the liquid composition to be inhaled intothe patient's lungs. Suitable formulations, wherein the carrier is aliquid, for administration, as for example, a nasal spray or as nasaldrops, include aqueous or oily solutions of the active ingredient.

Formulations suitable for nasal administration, wherein the carrier is asolid, include a coarse powder having a particle size, for example, inthe range of 20 to 500 microns which is administered in the manner inwhich snuff is administered (i.e., by rapid inhalation through the nasalpassage from a container of the powder held close up to the nose).Suitable powder compositions include, by way of illustration, powderedpreparations of the active ingredient thoroughly intermixed with lactoseor other inert powders acceptable for intrabronchial administration. Thepowder compositions can be administered via an aerosol dispenser orencased in a breakable capsule which may be inserted by the patient intoa device that punctures the capsule and blows the powder out in a steadystream suitable for inhalation.

Modulators may also be prepared in the form of suppositories (e.g., forrectal administration). Such compositions can be prepared by mixing thedrug with a suitable non-irritating excipient that is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Pharmaceutical compositions may be formulated as sustained releaseformulations (i.e., a formulation such as a capsule that effects a slowrelease of modulator following administration). Such formulations maygenerally be prepared using well known technology and administered by,for example, oral, rectal or subcutaneous implantation, or byimplantation at the desired target site. Carriers for use within suchformulations are biocompatible, and may also be biodegradable;preferably the formulation provides a relatively constant level ofmodulator release. The amount of modulator contained within a sustainedrelease formulation depends upon, for example, the site of implantation,the rate and expected duration of release and the nature of thecondition to be treated or prevented.

In addition to or together with the above modes of administration, amodulator may be conveniently added to food or drinking water (e.g., foradministration to non-human animals including companion animals (such asdogs and cats) and livestock). Animal feed and drinking watercompositions may be formulated so that the animal takes in anappropriate quantity of the composition along with its diet. It may alsobe convenient to present the composition as a premix for addition tofeed or drinking water.

Modulators are generally administered in a therapeutically effectiveamount. Preferred systemic doses range from about 0.1 mg to about 140 mgper kilogram of body weight per day (about 0.5 mg to about 7 g perpatient per day), with oral doses generally being about 5-20 fold higherthan intravenous doses. The amount of active ingredient that may becombined with the carrier materials to produce a single dosage form willvary depending upon the host treated and the particular mode ofadministration. Dosage unit forms will generally contain between fromabout 1 mg to about 500 mg of an active ingredient.

Packaged pharmaceutical compositions are also provided herein,comprising a therapeutically effective amount of at least one C5areceptor antagonist in a container (preferably sealed) and instructionsfor using C5a receptor antagonist to treat a condition responsive to C5areceptor modulation (e.g., rheumatoid arthritis, psoriasis,cardiovascular disease, reperfusion injury, bronchial asthma,chronic'pulmonary obstructive disorder (COPD), cystic fibrosis,Alzheimer's disease, stroke, myocardial infarction, atherosclerosis,ischemic heart disease or ischemia-reperfusion injury). The activeagent(s) may be formulated for administration in a single pharmaceuticalpreparation (e.g., within the same pharmaceutical composition).Alternatively, each of the active agents may be formulated for separateadministration, by the same or different routes of administration.Within a packaged pharmaceutical preparation, a therapeuticallyeffective amount may be packaged as a single dose unit; alternatively,multiple doses may be packaged together for convenience. The C5areceptor modulator may be presented in any suitable container including,but not limited to, a plastic, paper, metal or glass package such as anampoule, bottle, vial, blister package, infusion bag, syringe, inhaleror tube. For example, a packaged pharmaceutical preparation for oraladministration of an active agent may comprise a blister packagecontaining rows of tablets. Instructions may be present on a labelattached to the container or on exterior packaging, or may be providedas a package insert.

Methods of Use

C5a modulators provided herein may be used as agonists or (preferably)antagonists, such as inverse agonists, of C5a receptors in a variety ofcontexts, both in vitro and in vivo. Within certain aspects, C5a′antagonists may be used to inhibit the binding of C5a receptor ligand(e.g., C5a) to C5a receptor in vitro or in vivo. In general, suchmethods comprise the step of contacting a C5a receptor with a sufficientconcentration of one or more C5a receptor modulators, as providedherein, in the presence of C5a receptor ligand in aqueous solution andunder conditions otherwise suitable for binding of the ligand to C5areceptor. The C5a receptor may be present in suspension (e.g., in anisolated membrane or cell preparation), or in a cultured or isolatedcell. Within certain embodiments, the C5a receptor is expressed by acell present in a patient, and the aqueous solution is a body fluid. Ingeneral, the concentration of C5a receptor modulator contacted with thereceptor should be sufficient to inhibit C5a binding to C5a receptor invitro as measured, for example, using a calcium mobilization assay orchemotaxis assay as described herein.

Also provided herein are methods for modulating, preferably inhibiting,the signal-transducing activity of a C5a receptor. Such modulation maybe achieved by contacting a C5a receptor (either in vitro or in vivo)with a therapeutically effective amount of one or more C5a receptormodulators provided herein under conditions suitable for binding of themodulator(s) to the receptor. The receptor may be present in solution orsuspension, in a cultured or isolated cell preparation or within apatient. Modulation of signal transducing activity may be assessed bydetecting an effect on calcium ion conductance (also referred to ascalcium mobilization or flux) or by detecting an effect on C5areceptor-mediated cellular chemotaxis. C5a receptor modulator(s)provided herein are preferably administered to a patient (e.g., a human)orally or topically, and are present within at least one body fluid ofthe animal while modulating C5a receptor signal-transducing activity.

The present invention further provides methods for treating patientssuffering from conditions responsive to C5a receptor modulation. As usedherein, the term “treatment” encompasses both disease-modifyingtreatment and symptomatic treatment, either of which may be prophylactic(i.e., before the onset of symptoms, in order to prevent, delay orreduce the severity of symptoms) or therapeutic (i.e., after the onsetof symptoms, in order to reduce the severity and/or duration ofsymptoms). A condition is “responsive to C5a receptor modulation” ifmodulation of C5a receptor activity results in alleviation of thecondition or a symptom thereof. Patients may include primates(especially humans), domesticated companion animals (such as dogs, cats,horses) and livestock (such as cattle, pigs, sheep), with dosages asdescribed herein.

Conditions that are responsive to C5a receptor modulation include thefollowing:

Autoimmune disorders—e.g., rheumatoid arthritis, systemic lupuserythematosus (and associated glomerulonephritis), psoriasis, Crohn'sdisease, irritable bowel syndrome, dermatomyositis, multiple sclerosis,bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis,autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome(and associated glomerulonephritis and pulmonary hemorrhage), tissuegraft rejection, and hyperacute rejection of transplanted organs.

For asthma therapy, C5a receptor antagonists provided herein may be usedto prevent or decrease the severity of both acute early phase asthmaattack and the late phase reactions that follow such an asthma attack.

Inflammation, Inflammatory disorders and related conditions—e.g.,neutropenia, sepsis, septic shock, Alzheimer's disease, stroke,inflammation associated with severe burns, lung injury, andischemia-reperfusion injury, osteoarthritis, as well as acute (adult)respiratory distress syndrome (ARDS), chronic pulmonary obstructivedisorder (COPD), systemic inflammatory response syndrome (SIRS),neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wellssyndrome, lichen planus, familial cold autoinflammatory syndrome (FCAS).inflammatory bowel disease (IBD), colitis, cystic fibrosis, rupturedabdominal aortic aneurysm and multiple organ dysfunction syndrome(MODS). Also included are pathologic sequellae associated withinsulin-dependent diabetes mellitus (including diabetic retinopathy),lupus nephropathy, Heyman nephritis, membranous nephritis and otherforms of glomerulonephritis, contact sensitivity responses, andinflammation resulting from contact of blood with artificial surfacesthat can cause complement activation, as occurs, for example, duringextracorporeal circulation of blood (e.g., during hemodialysis or via aheart-lung machine, for example, in association with vascular surgerysuch as coronary artery bypass grafting or heart valve replacement) suchas extracorporeal post-dialysis syndrome, or in association with contactwith other artificial vessel or container surfaces (e.g., ventricularassist devices, artificial heart machines, transfusion tubing, bloodstorage bags, plasmapheresis, plateletpheresis, and the like).

Cardiovascular and Cerebrovascular Disorders—e.g., myocardialinfarction, coronary thrombosis, vascular occlusion, post-surgicalvascular reocclusion, atherosclerosis, traumatic central nervous systeminjury, and ischemic heart disease. For example, a therapeuticallyeffective amount of a compound provided herein may be administered to apatient at risk for myocardial infarction or thrombosis (i.e., a patientwho has one or more recognized risk factor for myocardial infarction orthrombosis, such as, but not limited to, obesity, smoking, high bloodpressure, hypercholesterolemia, previous or genetic history ofmyocardial infarction or thrombosis) in order reduce the risk ofmyocardial infarction or thrombosis.

Ocular Disorders—e.g., vascular retinopathies, ocular inflammation,age-related macular degeneration, proliferative vitreoretinopathy,Behcet's disease, vernal keratoconjunctivitis, retinal capillaryinfarction, retinal hemorrhage, prevention of ocular complicationsduring IFN-a therapy, and uveitis.

Vasculitis—e.g., immunovasculitis, microscopic polyangiitis,Churg-Strauss syndrome, Kawasaki syndrome, Wegener's granulomatosis andurticarial vasculitis.

HIV infection and AIDS—C5a receptor modulators provided herein may beused to inhibit HIV infection, delay AIDS progression or decrease theseverity of symptoms of HIV infection and AIDS.

In a further aspect, C5a receptor modulators may be used to perfuse adonor organ prior to transplantation of the organ into a recipientpatient. Such perfusion is preferably carried out using a solution(e.g., pharmaceutical composition) comprising a concentration of themodulator that is sufficient to inhibit C5a receptor-mediated effects invitro and/or in vivo. Such perfusion preferably reduces the severity orfrequency of one or more of the inflammatory sequelae following organtransplantation when compared to that occurring in control (including,without restriction, historical control) transplant recipients who havereceived transplants of donor organs that have not been so perfused.

Within further aspects, C5a antagonists provided herein may be used totreat Alzheimer's disease, multiple sclerosis, and cognitive functiondecline associated with cardiopulmonary bypass surgery and relatedprocedures. Such methods comprise administration of a therapeuticallyeffective amount of a C5a antagonist provided herein to a patientafflicted with one or more of the above conditions, or who is consideredto be at risk for the development of one or more such conditions.

In a further aspect, C5a receptor modulators of the current inventionmay be used in the treatment of disorders associated with pregnancyincluding antiphospholipid syndrome.

Suitable patients include those patients suffering from or susceptibleto a disorder or disease identified herein. Typical patients fortreatment as described herein include mammals, particularly primates,especially humans. Other suitable patients include domesticatedcompanion animals such as a dog, cat, horse, and the like, or alivestock animal such as cattle, pig, sheep and the like.

In general, treatment methods provided herein comprise administering toa patient a therapeutically effective amount of one or more compoundsprovided herein. Treatment regimens may vary depending on the compoundused and the particular condition to be treated; for treatment of mostdisorders, a frequency of administration of 4 times daily or less ispreferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex and diet of the patient, the time and routeof administration, the rate of excretion, any co-administered drugs andthe severity of the particular disease, as well as the judgment of theprescribing medical practitioner. In general, the use of the minimumdose sufficient to provide effective therapy is preferred. Patients maygenerally be monitored for therapeutic effectiveness using medical orveterinary criteria suitable for the condition being treated orprevented.

Certain treatment methods provided herein further comprise administeringto a patient a therapeutically effective amount of one or more compoundsor forms thereof provided herein in combination with at least oneanti-inflammatory or immunomodulatory pharmaceutical agent.

As noted above, certain compounds and compositions provided herein areuseful as inhibitors of C5a receptor-mediated chemotaxis (e.g., they maybe used as standards in assays of such chemotaxis). Accordingly, methodsare provided herein for inhibiting C5a receptor-mediated cellularchemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis. Suchmethods comprise contacting white blood cells (particularly primatewhite blood cells, especially human white blood cells) with one or morecompounds provided herein. Preferably the concentration is sufficient toinhibit chemotaxis of white blood cells in an in vitro chemotaxis assay,so that the levels of chemotaxis observed in a control assay aresignificantly higher, as described above, than the levels observed in anassay to which a compound as described herein has been added.

Dosage levels on the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orprevention of conditions involving pathogenic C5a activity (about 0.5 mgto about 7 g per human patient per day). The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. Dosage unit forms will generally contain betweenfrom about 1 mg to about 500 mg of an active ingredient. For compoundsadministered orally, transdermally, intravaneously, or subcutaneously,it is preferred that sufficient amount of the compound be administeredto achieve a serum concentration of 5 ng (nanograms)/mL-10 μg(micrograms)/mL serum, more preferably sufficient C5a receptor modulatorto achieve a serum concentration of 20 ng-1 μg/mL serum should beadministered, most preferably sufficient C5a receptor modulator toachieve a serum concentration of 50 ng/mL-200 ng/mL serum should beadministered. For direct injection into the synovium (for the treatmentof arthritis) sufficient C5a receptor modulator should be administeredto achieve a local concentration of approximately 1 micromolar.

Within separate aspects, the present invention provides a variety ofnon-pharmaceutical in vitro and in vivo uses for the compounds providedherein. For example, such compounds may be labeled and used as probesfor the detection and localization of C5a receptor (in samples such ascell preparations or tissue sections, preparations or fractionsthereof). Compounds may also be used as positive controls in assays forC5a receptor activity, as standards for determining the ability of acandidate agent to bind to C5a receptor, or as radiotracers for positronemission tomography (PET) imaging or for single photon emissioncomputerized tomography (SPECT). Such methods can be used tocharacterize C5a receptors in living subjects. For example, a C5areceptor modulator may be labeled using any of a variety of well knowntechniques (e.g., radiolabeled with a radionuclide such as tritium, asdescribed herein), and incubated with a sample for a suitable incubationtime (e.g., determined by first assaying a time course of binding).Following incubation, unbound compound is removed (e.g., by washing),and bound compound detected using any method suitable for the labelemployed (e.g., autoradiography or scintillation counting forradiolabeled compounds; spectroscopic methods may be used to detectluminescent groups and fluorescent groups). As a control, a matchedsample containing labeled compound and a greater (e.g., 10-fold greater)amount of unlabeled compound may be processed in the same manner. Agreater amount of detectable label remaining in the test sample than inthe control indicates the presence of C5a receptor in the sample.Detection assays, including receptor autoradiography (receptor mapping)of C5a receptor in cultured cells or tissue samples may be performed asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York.

Modulators provided herein may also be used within a variety of wellknown cell separation methods. For example, modulators may be linked tothe interior surface of a tissue culture plate or other support, for useas affinity ligands for immobilizing and thereby isolating, C5areceptors (e.g., isolating receptor-expressing cells) in vitro. Withinone preferred embodiment, a modulator linked to a fluorescent marker,such as fluorescein, is contacted with the cells, which are thenanalyzed (or isolated) by fluorescence activated cell sorting (FACS).

Preparation of Compounds

Representative methods for preparing 3-aryl-5,6-disubstituted pyridazinecompounds are shown in Schemes 1-2. Those skilled in the art willrecognize that the reagents and synthetic transformations in thefollowing Schemes can be readily modified to produce additionalcompounds of Formula I and Formula II. When a protecting group isrequired, an optional deprotection step may be employed. Suitableprotecting groups and methodology for protection and deprotection suchas those described in Protecting Groups in Organic Synthesis by T.Greene are well known. Compounds and intermediates requiringprotection/deprotection will be readily apparent.

Abbreviations used in the following Schemes and Examples are as follows:

-   -   Ac₂O acetic anhydride    -   BOP benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium        hexafluorophospate    -   n-BuLi n-butyl lithium    -   CDCl₃ deuterated chloroform    -   DCE 1,2-dichlorethane    -   DCM dichloromethane    -   DEAD diethyl azidocarboxylate    -   DIBAL-H diisobutylaluminum hydride    -   DIEA diiosopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMAP 4-N,N-dimethylaminopyridine    -   DMF N,N-dimethylformamide    -   DPPF 1,1′-bis(diphenylphosphino)ferrocene    -   EtOAc ethyl acetate    -   h hours    -   HOAc acetic acid    -   HPLC high pressure liquid chromatography    -   ¹H NMR proton nuclear magnetic resonance    -   Hz hertz    -   LAH lithium aluminum hydride    -   LDA lithium diisopropylamide    -   LC/MS liquid chromatography/mass spectrometry    -   MEK, methyl ethyl ketone (2-butanone)    -   MHz megahertz    -   min minutes    -   MS mass spectrometry    -   (M+1) mass+1    -   NMP N-methyl-2-pyrrolidone    -   NBS N-bromosuccinimde    -   δ chemical shift    -   Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium (0)    -   POCl₃ phosphorous oxychloride    -   PrMgCl n-propylmagnesium chloride    -   PTLC preparative thin layer chromatography    -   rt retention time    -   THF tetrahydrofuran    -   TMSCN trimethylsilylcyanide    -   18-C-6 18-crown-6

Scheme 1 illustrates a route for preparing compounds of Formula Iwherein R₂ is NR₄R₅ and R₁ and R₃ form a phenyl ring. An illustrativeexample for this scheme is published in WO 98/27066 as Example 9 and ishereby incorporated by reference.

Representative examples for the preparation of compounds of Formula Iand Formula II (and the other Formulas provided herein) by the methodsillustrated in the above Schemes are provided in the following Examples.Unless otherwise specified all starting materials and reagents are ofstandard commercial grade, and are used without further purification, orare readily prepared from such materials by routine methods. Thoseskilled in the art of organic synthesis will recognize that startingmaterials and reaction conditions may be varied to achieve the desiredend product.

EXAMPLES Example 1 Preparation of Certain Starting Materials A.Synthesis of 2,6-diethylphenylboronic acid

2,6-Diethyl bromobenzene (38.2 g, 180.2 mmol) is added dropwise throughan additional funnel over a 1 h period to a solution of n-BuLi (2.0 M incyclohexane, 99.1 mL, 198.2 mmol) in THF (380 mL) at −75° C. Afteraddition, the reaction mixture is stirred at −75° C. for 30 min;trimethyl borate (28.1 g, 270.3 mmol) is added slowly over a 40 minuteperiod. The reaction mixture is warmed to room temperature overnight. 2NHCl (250 mL) is added slowly and the resulting mixture is stirred for 1h. The organic layer is separated and the aqueous layer is extractedwith ether (2×200 mL). The combined organic layers are dried overanhydrous Na₂SO₄ and the solvents are removed in vacuo. Hexane (400 mL)is added to the residue and a white precipitate is formed. Filtrationand drying in vacuo give 2,6-diethylphenyl boronic acid as a whitesolid. ¹H NMR: (CDCl₃) 7.22 (t, 1H), 7.04 (s, 2H), 4.65 (s, 2H), 2.64(q, 4H), 1.22 (t, 6H).

B. Synthesis of 2,6-dimethyl-3-methoxybenzeneboronic acid

Step 1. Preparation of aldehyde

A solution of 2-bromo-m-xylene (4.2 g, 23 mmol) in dichloromethane (5mL) at −78° C. is added dropwise to a solution of titanium tetrachloride(5.0 mL, 45 mmol) and dichloromethyl methyl ether (2.3 mL, 25 mmol) indichloromethane (20 mL). After the addition is complete, the mixture isallowed to warm to room temperature and stirred for and additional 4 hbefore being poured onto ice water. The reaction is extracted withdichloromethane. The organic fraction is washed with water, dried(Na₂SO₄), and concentrated to give the aldehyde as a pale yellow solid,which is used in the next step without further purification: 1H NMR(CDCl₃) 10.1 (s, 1H), 7.68 (d, 1H), 7.22 (d, 1H), 2.79 (s, 3H), 2.45 (s,3H).

Step 2. Preparation of methyl ether

M-chloroperoxybenzoic acid (68%, 8.4 g, 33 mmol) is added to a solutionof the above aldehyde (4.7 g) in dichloromethane (120 mL). The mixtureis stirred at reflux overnight and concentrated in vacuo. The residue isdissolved in EtOAc and washed successively with saturated NaHCO₃ (3times), saturated NaBSO₃, and water. The organic fraction is dried(Na₂SO₄) and concentrated to give the crude formate. The formate istreated with potassium carbonate (4 g) in ethanol (80 mL) at roomtemperature for 20 min, followed by filtration and concentration to givethe corresponding alcohol. The crude alcohol is dissolved in acetone(160 mL) and dimethyl sulfate (2.7 mL, 29 mmol), and potassium carbonate(8.0 g, 58 mmol) is added. The mixture is stirred at reflux for 5 h.After cooling to room temperature, filtration, concentration, and flashchromatography provide the desired methyl ether as a colorless oil. ¹HNMR (CDCl₃) 7.02 (d, 1H), 6.73 (d, 1H), 3.80 (s, 3H), 2.37 (s, 3H), 2.35(s, 3H).

Step 3. Preparation of 2,6-dimethyl-3-methoxybenzeneboronic acid

A solution of 2,4-dimethyl-3-bromoanisole (3.3 g, 15 mmol) in THF (15mL) is added dropwise at −78° C. to a solution of n-butyllithium (11 mLof 1.6M in hexane, 17 mmol) in THF (35 mL). After 30 min, trimethylborate (2.3 mL, 20 mmol) is added and the mixture is allowed to warm toroom temperature overnight. The mixture is poured onto 10% HCl andextracted with EtOAc. The organic fraction is washed with saturatedbrine, dried (Na₂SO₄), and concentrated to give the desired product as abrownish oil. ¹H NMR (CDCl₃) 6.98 (d, 1H), 6.75 (d, 1H), 4.64 (br s),3.80 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).

F. Synthesis of (S)-Methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine

Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixtureof (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) andK₂CO₃ (18.8 g, 136 mmol) in CH₃CN (100 mL). The resulting mixture isstirred at room temperature overnight. Water (100 mL) is added and themixture is extracted with ether (2×100 mL). The combined extract iswashed with 1 N HCl (2×10 mL), water, dried (Na₂SO₄), and concentratedin vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acidethyl ester as a solid.

(1,2,3,4-Tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester (5.0 g,22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH₄ (2.6g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C.with stirring for 2 h. On cooling, Na₂SO₄.10H₂O (15.0 g) and ether (100mL) are added to the mixture. The resulting mixture is stirred at roomtemperature for 1 h, filtered through celite, and concentrated in vacuo.1 N HCl (20 mL) and ether (20 ML) are added to the residue. The organiclayer is separated and discarded. The aqueous layer is basified with 1 NNaOH and extracted with CH₂Cl₂ (2×25 mL). The combined extract is washedwith water (2×), dried (Na₂SO₄) and concentrated to give(S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine as an oil.[α]^(RT)=−10.6 (0.02, EtOH). ¹H NMR (CDCl₃) 7.30 (m, 1H), 7.06-7.20 (m,3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H).

Similar procedures are applied in the synthesis of the following amines:

-   (R)-Methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine;-   (S)-Ethyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine;-   (S)-Propyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine;-   (S)-Indan-1-yl-methyl-amine;-   (±)Methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine; and-   (±)Indan-1-yl-methyl-amine.

G. Synthesis of 5-Methylindole-4-boronic acid

Fuming nitric acid (>90% yellow fuming HNO₃) is slowly added to asolution of 2-bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 mL)cooled in an ice bath (above freezing point). The resulting mixture isallowed to warm to room temperature, stirred for 1 h, and heated at 80°C. for 2 h or until the reaction is complete by GC/MS analysis followingmicro-scale base work-up. The reaction mixture is cooled to roomtemperature and poured into ice/water with stirring. The resultingyellow precipitates are collected by suction filtration and air dried toobtain 2,6-dimethyl-3-nitrobromobenzene.

Bredereck's reagent (tert-butoxybis(dimethylamino)methane (16 g, 91mmol) is added to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g,87 mmol) in anhydrous DMF (120 mL) at room temperature. The reactionmixture is heated at 120-125° C. under N₂ for 5 h or until startingmaterial is mostly consumed according to TLC. The reaction mixture isallowed to cool to room temperature, poured into water (300 mL), andextracted with dichloromethane (100 mL×3). The combined extracts aredried over anhydrous sodium sulfate, filtered, and concentrated toobtain a mixture of enamines as a dark brown oil. This material is usedin the next step without purification.

The crude mixture is dissolved in acetic acid/water (250 mL of 4:1),cooled to 0° C. and treated with zinc dust (57 g, 870 mmol) added slowlyin portions. After complete addition, the reaction mixture is heated at110° C. for 4 h. Zinc is removed by filtration through a celite pad andthe filtrate is extracted with dichloromethane (100 mL×3). The combinedextracts are dried over anhydrous sodium sulfate, concentrated, andpurified by flash chromatography on silica gel (EtOAc/Hexane 1:20) toobtain 4-bromo-5-methylindole as a light purple oil.

A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrousether (8 mL) is added with stirring to a suspension of potassium hydride(560 mg, 4.2 mmol, 30% dispersion in mineral oil) in anhydrous ether at0° C. under argon. The resulting mixture is cooled to −78° C. andtert-butyllithium (4.9 mL of 1.7 M in pentane, 8.4 mmol) is slowlyadded. The resulting cream-colored mixture is stirred at −78° C. for 1h. Tributylborate (3.1 mL, 11.4 mmol) is slowly added and the reactionmixture is stirred for 1 h at −78° C. before being allowed to slowlywarm to room temperature. More anhydrous ether is added to facilitatestirring. After stirring for 24 h, the resulting sticky mixture isdiluted with ether and transferred in portions with stirring to aprecooled solution of 1 M phosphoric acid (50 mL). After stirring for 30min, the acidic mixture is extracted with diethyl ether (75 mL×3) andthe combined extracts are extracted with 1 N sodium hydroxide (20 mL×4).The combined base extracts are cooled with an ice bath, acidified with 1M phosphoric acid and extracted with EtOAc (20 mL×3). The combinedextracts are washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated to obtain a beige residue. Theresidue is triturated with hexane to obtain the desired5-methylindole-4-boronic acid as a beige gum.

H. Synthesis of 6-isopropyl-2-methyl-3-nitrobenzeneboronic acid

6-Isopropyl-2-methylbenzeneboronic acid (8 g) is added portionwise over1 h to 90% HNO₃ (50 mL) at −40° C., maintaining an internal temperaturebelow −30° C. After addition, the mixture is stirred at −40 to −30° C.for 15 min, then poured onto ice, and diluted with water. The solid iscollected by filtration, washed with water and dried to give6-isopropyl-2-methyl-3-nitrobenzeneboronic acid as a white solid. ¹H NMR(DMSO-d6) 7.78 (d, 2H), 7.30 (d, 2H), 2.85 (m, 1H), 2.38 (s, 3H), 1.15(d, 6H).

1. Synthesis of 5-Isopropyl-1H-Indazole-4-Boronic Acid

Step 1. Preparation of 4-Bromo-5-isopropyl-1H-indazole

Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of2-isopropyl-6-methyl-bromobenzene (10 g, 213 mmol) in acetic acid (60mL). The mixture is heated 1 h at 90° C. and cooled to room temperature.The reaction mixture is poured into 200 mL ice-water and extracted withCH₂Cl₂ (3×60 mL). The combined extracts are washed with 1 N NaOH (3×40mL) and then water (40 mL), dried (Na₂SO₄), and concentrated to yieldcrude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved inAcOH (75 mL)/EtOH (75 mL). To this is added Fe power (5.3 g, 95 mmol)and the mixture is refluxed for 2 h. The mixture is cooled to roomtemperature, diluted with water, and neutralized with solid Na₂CO₃. Themixture is extracted with EtOAc, dried (Na₂SO₄), and concentrated invacuo. The residue is purified by flash chromatography (elution withHex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solutionof NaNO₂ (798 mg, 12 mmol) in H₂O (10 mL) is added dropwise at 0° C. toa slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) inHBF₄ (15 mL)-H₂O (15 mL), and the mixture is stirred for 1 h at 0° C.The resulting solid is filtered, washed with cold water and then Et₂O,and dried under reduced pressure to yield the diazonium salt as a beigesolid. The diazonium salt is added in one portion to mixture of KOAc(1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHCl₃ (70mL) at room temperature. The mixture is stirred for 1 h and theresulting solid is removed by filtration. The filtrate is washed withwater, dried (Na₂SO₄), and concentrated in vacuo. The residue ispurified by flash chromatography (elution with Hex/EtOAc 4:1) to yield4-bromo-5-isopropyl-1H-indazole. ¹H NMR (CDCl₃) 8.03 (br s, 1H), 7.41(d, 1H), 7.35 (d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).

Step 2. Preparation of 5-Isopropyl-1H-indazole-4-boronic acid

A solution of 4-bromo-5-isopropyl-1H-indazole (1.6 g, 6.9 mmol) in Et₂O(4 mL) is added slowly to a suspension of KH (1.0 g of 30% dispersion inmineral oil, 7.7 mmol) in Et₂O (20 mL) at 0° C. and the mixture isstirred for 20 min. After cooling to −78° C., i-BuLi (8.9 mL of 1.7 M inHex, 15 mmol) is added and the resulting mixture is stirred for 40 minat −78° C. To this is added B(On-Bu)₃ (5.6 mL, 21 mmol) and the mixtureis stirred for 24 h at room temperature. The reaction mixture isquenched with 1N H₃PO₄ and extracted with Et₂O. The combined Et₂O layersare back-extracted with 1N NaOH (3×10 mL). The combined NaOH extractsare acidified with 1N H₃PO₄ and extracted with EtOAc. The EtOAc extractsare washed with saturated brine, dried (MgSO₄), and concentrated toyield 5-isopropyl-1H-indazole-4-boronic acid. ¹H NMR (CDCl₃) 7.85 (s,1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d,6H).

J. Synthesis of 3-Isopropyl-1H-Indazole-4-Boronic Acid

Step 1. Preparation of 1-(2-Bromo-6-fluoro-phenyl)-2-methyl-propan-1-one

To a solution of n-BuLi (25 mL of 1.6 M solution in hexane, 40 mmol) inTHF (100 mL) is added 2,2,6,6-teramethylpiperidine (6.8 mL, 40 mmol) at−78° C. and the mixture is stirred for 20 min. To this is added3-bromofluoroebnzene (7.0 g, 40 mmol). After stirring for 3 h at −78°C., DMF (15 mL, 200 mmol) is added and the mixture is warmed to roomtemperature and stirred for 1 h. The mixture is quenched with 1N HCl andextracted with EtOAc. The combined extracts are dried (MgSO₄) andconcentrated in vacuo. The residue is purified by flash chromatography(elution with Hex/EtOAc 10:1) to yield 2-bromo-6-fluoro-benzaldehyde. ¹HNMR (CDCl₃) 10.4 (s, 1H), 7.48-7.39 (m, 2H), 7.18-7.14 (m, 1H).

Isopropylmagnesium chloride (18 mL of 2 M in Et₂O, 35 mmol) is added toa solution of 2-bromo-6-fluoro-benzaldehyde (6.0 g, 30 mmol) in THF (40mL) at −78° C. and the mixture is stirred for 1 h at 0° C. The mixtureis poured into saturated NH₄Cl and extracted with EtOAc. The resultingcrude alcohol is oxidized directly by Swern oxidation to yield1-(2-bromo-6-fluoro-phenyl)-2-methyl-1-one. ¹H NMR (CDCl₃) 7.38 (d, 1H),7.22 (m, 1H), 7.03 (t, 1H), 3.10 (m, 1H), 1.11 (d, 6H).

Step 2. Preparation of 3-Isopropyl-1H-indazole-4-boronic acid

A mixture of 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one (1.1 g,4.5 mmol) and anhydrous hydrazine (0.17 mL, 5.4 mmol) in ethylene glycol(10 mL) is heated for 16 h at 160° C. Water is added and the mixture isextracted with CH₂Cl₂. The combined extracts are dried (MgSO₄) andconcentrated in vacuo. The residue is purified by flash chromatographyto yield 4-bromo-3-isopropyl-1H-indazole. ¹H NMR (CDCl₃) 10.1 (br s,1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.17 (t, 1H), 3.99 (m, 1H), 1.43 (d,6H).

4-Bromo-3-isopropyl-1H-indazole is converted to the correspondingboronic acid following analogous procedures to that given in thepreceding example. ¹H NMR (CD₃OD) 7.44 (d, 1H), 7.32 (t, 1H), 7.05 (d,1H), 3.56 (m, 1H), 138 (d, 6H). LCMS (m/z): 205.45 (MH)⁺

Example 2 Synthesis of[4-Cyclobutyl-6-(2,6-dimethyl-phenyl)-pyridazin-3-yl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amineStep 1. Synthesis of 3-(2,6-dimethyl-phenyl)-6-methoxy-pyridazine

Sodium (4.8 g, 0.21 mol) is added portion-wise to MeOH (200 ml) withstirring. After a clear solution is formed, it is added slowly to asolution of 3,6-dichloro-pyridazine (29.6 g, 0.2 mol) in MeOH (200 ml).After addition, the mixture is heated at reflux for 3 h, then cooled andconcentrated under reduced pressure. EtOAc and water are added. Theorganic layer is separated, dried and concentrated under reducedpressure to give 26.4 g of 3-chloro-6-methoxy-pyridazine as a whitesolid.

A mixture of 3-chloro-6-methoxy-pyridazine (1.44 g, 10 mmol),2,6-methyl-phenyl boronic acid (1.73 g, 11.5 mmol), sodium carbonate (2M aqueous solution, 10.5 ml, 21 mmol), ethanol (2 ml) and Pd(PPh₃)₄ (232mg, 0.2 mmol) is refluxed in toluene (60 ml) overnight and then cooledto room temperature. EtOAc (20 ml) is added to the mixture and theorganic layer is separated. The organic layer is washed with water,dried, and solvent removed. The crude product is purified by flashsilica gel column (Hexanes/EtOAc 4:1) to give3-(2,6-dimethyl-phenyl)-6-methoxy-pyridazine. ¹H NMR: (CDCl₃) 7.21-7.30(m, 2H), 7.12 (d, 2H), 7.03 (d, 2H), 4.20 (s, 3H), 2.05 (s, 6H).

Step 2. Synthesis of 3-Chloro-6-(2,6-dimethyl-phenyl)-pyridazine

A mixture of 3-(2,6-dimethyl-phenyl)-6-methoxy-pyridazine (1.6 g, 7.47mmol) in hydriodic acid (57% in water, 10 mL) is heated at 80° C. for2.5 h. The cooled mixture is diluted with water, neutralized to pH 7with ammonium hydroxide and extracted with EtOAc. The extract is washedwith water, dried and concentrated to yield6-(2,6-dimethyl-phenyl)-pyridazin-3-ol as a solid.

A mixture of 6-(2,6-dimethyl-phenyl)-pyridazin-3-ol in POCl₃ is heatedat 80° C. for 2 h. The volatile material is evaporated under reducedpressure and the residue is partitioned between EtOAc and diluted NaOHaqueous solution. The organic layer is separated and the aqueous layeris extracted with EtOAc once. The combined organic extract is washedwith brine, dried and concentrated in vacuo. The crude product ispurified by flash column (Hexanes/EtOAc 4:1) to give3-chloro-6-(2,6-dimethyl-phenyl)-pyridazine. ¹H NMR: (CDCl₃) 7.59 (d,1H), 7.38 (d, 1H), 7.25 (m, 1H), 7.14 (d, 2H), 2.06 (s, 6H).

Step 3. Synthesis of3-Chloro-4-cyclobutyl-6-(2,6-dimethyl-phenyl)-pyridazine

A mixture of 3-chloro-6-(2,6-dimethyl-phenyl)-pyridazine (210 mg, 0.78mmol), cyclobutanecarboxylic acid (120 mg, 1.2 mmol), concentrated H₂SO₄(300 mg) and water (3 mL) is degassed with N₂ at 70° C. for 20 min.AgNO₃ (34 mg, 0.2 mmol) is added followed by dropwise addition of asolution of ammonium persulfate (210 mg, 0.92 mmol) in water. Thereaction mixture is stirred at the same temperature for one h. Aftercooled, the mixture is poured onto ice and water, neutralized withammonium hydroxide to pH 8-9 and extracted with EtOAc. The extract iswashed with water, dried and concentrated. The crude product is purifiedby flash silica gel column (Hexanes/EtOAc 4:1) to give3-Chloro-4-cyclobutyl-6-(2,6-dimethyl-phenyl)-pyridazine as an oil. ¹HNMR: (CDCl₃) 7.26 (m, 2H), 7.14 (d, 2H), 3.78 (m, 1H), 2.48 (m, 2H),2.00-2.20 (m, 9H), 1.90 (m, 1H).

Step 4. Synthesis of the Title Compound

To a solution of3-chloro-4-cyclobutyl-6-(2,6-dimethyl-phenyl)-pyridazine (81 mg, 0.3mmol) in 3 mL of ethylene glycol dimethyl ether is added a solution ofmethyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine in toluene (0.2M, 1.8mL) followed by dropwise addition of a solution of MeMgBr in THF (1.0 M,0.6 mL). The reaction mixture is stirred at 60° C. overnight. Aftercooled, water and EtOAc are added to the mixture. The organic layer isseparated, washed with water, dried, and concentrated in vacuo. Thecrude product is purified by PTLC (Hexanes/EtOAc 4:1) to give4-cyclobutyl-6-(2,6-dimethyl-phenyl)-pyridazin-3-yl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine.¹H NMR: (CDCl₃) 7.60 (d, 1H), 7.10-7.30 (m, 6H), 5.05 (m, 1H), 3.75 (m,1H), 2.70-2.90 (4H), 2.40 (m, 2H), 1.60-2.30 (m, 15H).

Example 3 Synthesis ofChroman-4-yl-[4-(2,6-dimethyl-phenyl)-5,6,7,8-tetrahydro-phthalazin-1-yl]-methyl-amineStep 1. Synthesis of 1,4-dichloro-5,6,7,8-tetrahydro-phthalazine

A mixture of 3,4,5,6-tetrahydrophthalic anhydride (3.5 g, 23 mmol),hydrazine hydrate (2.0 mL), sodium acetate (15.4 g, 188 mmol) in 100 mLof acetic acid is heated at 100° C. overnight. Upon cooling, a whitesolid is formed and collected by filtration. The solid is washed withwater and dried to give 2,3,5,6,7,8-hexahydro-phthalazine-1,4-dione. Thesolid is taken up in 15 mL of POCl₃. The resultant mixture is heated atreflux overnight. After cooled, the excess POCl₃ is removed underreduced pressure. Crushed ice is added to the residue followed bycareful addition of solid Na₂CO₃ to pH 9. The product is extracted withEtOAc twice. The combined extract is washed with brine, dried andconcentrated. The residue is purified by flash silica gel column(Hexanes/EtOAc 4:1) to give 1,4-dichloro-5,6,7,8-tetrahydro-phthalazineas a white solid. ¹H NMR: (CDCl₃) 2.74 (m, 4H), 1.87 (m, 4H).

Step 2. Synthesis of1-(2,6-dimethyl-phenyl)-4-methoxy-5,6,7,8-tetrahydro-phthalazine

In analogy to Example 2 Step 1,1,4-dichloro-5,6,7,8-tetrahydro-phthalazine is converted to1-(2,6-dimethyl-phenyl)-4-methoxy-5,6,7,8-tetrahydro-phthalazine as acolorless oil, ¹H NMR: (CDCl₃) 7.12 (t, 1H), 7.09 (d, 2H), 4.17 (s, 3H),2.65 (t, 2H), 2.14 (t, 2H), 1.96 (s, 6H), 1.60-1.85 (m, 4H).

Step 3. Synthesis of1-Chloro-4-(2,6-dimethyl-phenyl)-5,6,7,8-tetrahydro-phthalazine

In analogy to Example 2 Step2,1-(2,6-dimethyl-phenyl)-4-methoxy-5,6,7,8-tetrahydro-phthalazine isconverted to1-chloro-4-(2,6-dimethyl-phenyl)-5,6,7,8-tetrahydro-phthalazine as awhite solid, ¹H NMR: (CDCl₃) 7.22 (t, 1H), 7.12 (d, 2H), 2.80 (t, 2H),2.21 (t, 2H), 1.94 (s, 6H), 1.57-1.87 (m, 4H).

Step 4. Synthesis of the Tilted Compound

By analogy to Example 2 Step4,1-Chloro-4-(2,6-dimethyl-phenyl)-5,6,7,8-tetrahydro-phthalazine isconverted toChroman-4-yl-[4-(2,6-dimethyl-phenyl)-5,6,7,8-tetrahydro-phthalazin-1-yl]-methylamine,as an oil, LC-MS: 400.5 (m+1).

Example 4 General method for preparation of 1-amino-4-aryl phthalazinesin table I

Step 1. Synthesis of 1-amino-4-chloro-phthalazines

A mixture containing 4 mL of 0.5 M 1,4-dichlorophthalazine in DMA, 2equivalents of amine and 500 mg of KF is heated in a sealed vial at 100°C. overnight. Purification on silica gel and evaporation provides thedesired 1-amino-4-chloro-phthalazine.

Step 2. Synthesis of 1-amino-4-aryl-phthalazines

A mixture of 1-amino-4-chloro-phthalazine (0.1 mL of 0.2 M in toluene)is combined with aryl boronic acid (0.15 mL of 0.2 M in dioxane) andpotassium phosphate (0.05 mL of 1 M aqueous solution). The reactionmixture is placed in a glove box under nitrogen, Pd(PPh₃)₄ (0.05 mL of0.01 M solution in toluene) is added and the reaction mixture is heatedwith agitation at 75° C. for 18 h. Purification on an SCX cartridgeeluting with MeOH (5 mL) followed by 10:1 EtoAc/Et₃N (5 mL) provides,after evaporation of solvent, the desired 1-amino-4-aryl-phthalazine.

Example 5 Preparation of 1-amino-4-aryl phthalazines in table I

1-Aryl-4-chlorophthalazine (0.2 mL of 0.15 M in DME) [obtained asdescribed in Scheme 1] is combined with secondary amine (0.18 mL of 0.2M in toluene) and transferred to a glove box under nitrogen. Methylmagnesium bromide (0.75 mL of 1 M in THF) is added and the reactionmixture is heated at 75° C. for 18 h with agitation. Trifluoroaceticacid (50 μL of 1:1 with toluene) is added and the reaction mixture ispurified on an SCX cartridge eluting with EtOAc (5 mL) followed by10:1:1 EtOAc/MeOH/Et₃N (5 mL). Evaporation provides the desired1-amino-4-aryl-phthalazine. In some cases, further purification bychromatography on silica gel is needed.

Example 6 Additional 3-aryl-5,6-disubstituted pyridazines

The compounds shown in Table I are prepared according to the proceduresgiven in the above Schemes and further illustrated in the aboveExamples. All compounds in Table I and in Examples 1-3 exhibit an IC₅₀of 2 micromolar or less in the calcium mobilization assay provided inExample 16, herein.

LC/MS data is provided in Tables I along with retention time in minutesand a number (1, 2 or 3) indicating the method used. The LC/MS methodsare as follows:

Method 1:

-   -   Analytical HPLC/MS instrumentation: Analyses are performed using        a Waters 600 series pump (Waters Corporation, Milford, Mass.), a        Waters 996 Diode Array Detector and a Gilson 215 auto-sampler        (Gilson Inc, Middleton, Wis.), Micromass® LCT time-of-flight        electrospray ionization mass analyzer. Data are acquired using        MassLynx™ 4.0 software, with OpenLynx Global Server™, OpenLynx™,        and AutoLynx™ processing.    -   Analytical HPLC conditions: 4.6×50 mm, Chromolith™ SpeedROD        RP-18e column (Merck KGaA, Darmstadt, Germany); UV 10        spectra/sec, 220-340 nm summed; flow rate 6.0 mL/min; injection        volume 1 μl;        -   Gradient conditions—mobile phase A is 95% water, 5% methanol            with 0.05% TFA; mobile phase B is 95% methanol, 5% water            with 0.025% TFA, and the gradient is 0-0.5 min 10-100% B,            hold at 100% B to 1.2 min, return to 10% B at 1.21 min            inject-to-inject cycle time is 2.15 min.    -   Analytical MS conditions: capillary voltage 3.5 kV; cone voltage        30V; desolvation and source temperature are 350° C. and 120° C.,        respectively; mass range 181-750 with a scan time of 0.22        seconds and an inter scan delay of 0.05 min.

Method 2:

-   -   HPLC instrumentation: Analyses are performed using a Waters 600        series pump (Waters Corporation, Milford, Mass.), a Waters 996        Diode Array Detector and a Gilson 215 autosampler (Gilson Inc,        Middleton, Wis.). Data are acquired using MassLynx 4.0 software,        with OpenLynx processing.    -   HPLC conditions: 4.6×50 mm, Chromolith SpeedRod column (Merck        AEG); UV 5 spectra/sec, 220, 254 nm; flow rate 6.0 ml/min;        injection volume 1-10 μl;        -   Gradient conditions—Mobile phase A 95% Water, 5% Methanol            with 0.05% Formic acid; Mobile phase B 95% Methanol, 5%            Water with 0.025% Formic acid;

Gradient: Time(mins) % B 0 5 0.01 5 1.0 100 2 100 2.1 5

-   -   MS instrumentation: LC-MS experiments are performed using a        Waters ZMD II Mass Spectrometer.    -   MS conditions: Electrospray positive ionization; capillary        voltage 3.5 kV; cone voltage 30V; desolvation and source        temperature 250° C. and 100° C. respectively; mass range 120-800        with a scan time of 0.5 seconds and an inter scan delay of 0.1        mins.

Method 3:

-   -   HPLC instrumentation: Analyses are performed using a Waters 600        series pump (Waters Corp.), a Waters 996 Diode Array Detector        and a Gilson 215 autosampler (Gilson Inc.). Data are acquired        using MassLynx 4.0 software, with OpenLynx processing.    -   HPLC conditions: 4.6×50 mm, XTerra MS C18, 5 μm column (Waters        Corp.); UV 10 spectra/sec, 220, 254 nm; flow rate 4.0 mL/min;        injection volume 1-10 μl;        -   Gradient conditions—Mobile phase A 95% Water, 5% Methanol            with 0.05% Formic acid; Mobile phase B 95% Methanol, 5%            Water with 0.025% Formic acid;

Gradient: Time(mins) % B 0 5 0.01 5 2.0 100 3.50 100 3.51 5

-   -   MS instrumentation: LC-MS experiments are performed using a        Waters ZMD II Mass Spectrometer.    -   MS conditions: Electrospray positive ionization; capillary        voltage 3.5 kV; cone voltage 30V; desolvation and source        temperature 250° C. and 100° C. respectively; mass range 120-800        with a scan time of 0.5 seconds and an inter scan delay of 0.1        mins.

TABLE 1 LCMS Retention LCMS LCMS Time Mass M + H Cpd # Structure Name(min) (amu) (amu) 1

N-(cyclopropylmethyl)-4- mesityl-N- propylphthalazin-1-amine 1.15 359.2360.3 2

4-mesityl-N,N- dipropylphthalazin-1- amine 1.14 347.2 348.3 3

4-(4-methoxyphenyl)-N,N- dipropylphthalazin-1- amine 1.11 335.2 336.2 4

4-(4-chlorophenyl)-N- (cyclopropylmethyl)-N- propylphthalazin-1-amine1.14 351.2 352.2 5

N-(cyclopropylmethyl)-4- (2-methylphenyl)-N- propylphthalazin-1-amine1.12 331.2 332.2 6

4-(5-chloro-2- methoxyphenyl)-N- (cyclopropylmethyl)-N-propylphthalazin-1-amine 1.12 381.2 382.2 7

N-(cyclopropylmethyl)-4- (1-naphthyl)-N- propylphthalazin-1-amine 1.14367.2 368.2 8

N-methyl-4-(2- methylphenyl)-N-(1- phenylethyl)phthalazin-1- amine 9

4-(5-chloro-2- methoxyphenyl)-N- methyl-N-(1- phenylethyl)phthalazin-1-amine 10

4-(2-fluorophenyl)-N- methyl-N-(1- phenylethl)phthalazin-1- amine 11

4-(2-methylphenyl)-N,N- dipropylphthalazin-1- amine 12

4-(5-chloro-2- methoxyphenyl)-N,N- dipropylphthalazin-1- amine 13

N-butyl-4-(5-chloro-2- methoxyphenyl)-N- ethylphthalazin-1-amine 14

N-methyl-4-(1-naphthyl)- N-(1- phenylethyl)phthalazin-1- amine 1.14389.2 390.2 15

4-(2-chlorophenyl)-N- methyl-N-(1- phenylethyl)phthalazin-1- amine 1.14373.1 374.2 16

N-methyl-N-(1- phenylethy)-4-[2- (trifluoromethyl)phenyl]phthalazin-1-amine 1.15 407.2 408.2 17

4-(1-naphthyl)-N,N- dipropylphthalazin-1- amine 1.13 355.2 356.3 18

4-(2-chlorophenyl)-N,N- dipropylphthalazin-1- amine 1.11 339.2 340.2 19

N-butyl-N-ethyl-4-(1- naphthyl)phthalazin-1- amine 1.14 355.2 356.3 20

N-benzyl-4-(2- chlorophenyl)-N- ethylphthalazin-1-amine 1.14 373.1 374.221

N-benzyl-N-ethyl-4-[2- (trifluoromethyl)phenyl] phthalazin-1-amine 1.16407.2 408.2 22

4-mesityl-N-methyl-N- [(1S)-1- phenylethyl]phthalazin-1- amine 1.15381.2 382.3 23

4-mesityl-N-methyl-N-(1- phenylbutyl)phthalazin-1- amine 1.19 409.3410.3 24

4-mesityl-N-methyl-N-(2- methyl-1- phenylpropyl)phthalazin- 1-amine 1.19409.3 410.3 25

N-(2,3-dihydro-1H-inden- 1-yl)-4-mesityl-N- methylphthalazin-1-amine1.17 393.2 394.3 26

N-benzyl-N-ethyl-4- mesitylphthaiazin-1-amine 1.16 381.2 382.3 27

N-benzyl-N-isobutyl-4- mesitylphthalazin-1-amine 1.2 409.3 410.3 28

4-mesityl-N-(2- phenylethyl)-N- propylphthalazin-1-amine 1.17 409.3410.3 29

4-(2,4-dimethoxyphenyl)- N-methyl-N-(1- phenylethyl)phthalazin-1- amine1.11 399.2 400.2 30

4-(2,4-dimethoxyphenyl)- N-methyl-N-(1- phenylbutyl)phthalazin-1- amine1.15 427.2 428.3 31

4-(2,4-dimethoxyphenyl)- N-methyl-N-(2-methyl-1-phenylpropyl)phthalazin- 1-amine 1.14 427.2 428.3 32

N-(2,3-dihydro-1H-inden- 1-yl)-4-(2,4- dimethoxyphenyl)-N-methylphthalazin-1-amine 1.13 411.2 412.3 33

4-(2,4-dimethoxyphenyl)- N-(2-phenylethyl)-N- propylphthalazin-1-amine1.14 427.2 428.3 34

3-methyl-4-(4- {methyl[(1S)-1- phenylethyl]amino} phthalazin-1-yl)phenol 1.1 369.2 370.1 35

3-methyl-4-{4-[methyl(1- phenylbutyl)amino] phthalazin-1-yl}phenol 1.13397.2 398.1 36

3-methyl-4-{4-[methyl(2- methyl-1- phenylpropyl)amino]phthalazin-1-yl}phenol 1.14 397.2 398.1 37

4-{4-[2,3-dihydro-1H- inden-1- yl(methyl)amino] phthalazin-1-yl}-3-methylphenol 1.1 381.2 382.1 38

4-{4- [benzyl(ethyl)amino] phthalazin-1-yl}-3- methylphenol 1.1 369.2370.1 39

4-{4- [(cyclopropylmethyl) (propyl)amino] phthalazin-1-yl}-3-methylphenol 1.09 347.2 348.1 40

3-methyl-4-{4-[(2- phenylethyl)(propyl)amino] phthalazin-1-yl}phenol1.11 397.2 398.1 41

4-{4- [cyclohexyl(ethyl)amino] phthalazin-1-yl}-3- methylphenol 1.11361.2 362.1 42

4-mesityl-N-methyl-N-(1- phenylethyl)phthalazin-1- amine 1.15 381.2382.1 43

4-mesityl-N-methyl-N- [(1R)-1- phenylethyl]phthalazin-1- amine 1.15381.2 382.1 44

4-mesityl-N-methyl-N-(1- phenylpropyl)phthalazin- 1-amine 1.17 395.2396.3 45

N-cyclohexyl-4-mesityl-N- methylphthalazin-1-amine 1.15 359.2 360.3 46

4-mesityl-N-methyl-N- (1,2,3,4- tetrahydronaphthalen-1-yl)phthalazin-1-amine 1.19 407.2 408.3 47

4-mesityl-N-methyl-N- (6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-yl)phthalazin-1-amine 1.19 421.3 422.3 48

3-methyl-4-{4-[methyl(1- phenylethyl)amino] phthalazin-1-yl}phenol 1.1369.2 370.2 49

3-methyl-4-(4- {methyl[(1R)-1- phenylethyl]amino} phthalazin-1-yl)phenol1.09 369.2 370.2 50

3 -methyl-4-{4-methyl(1- phenylpropyl)amino] phthalazin-1-yl}phenol 1.11383.2 384.3 51

4-{4- [cyclohexyl(methyl)amino] phthalazin-1-yl}-3- methylphenol 1.09347.2 348.3 52

3-methyl-4-{4- [methyl(1,2,3,4- tetrahydronaphthalen-1-yl)amino]phthalazin-1- yl}phenol 1.13 395.2 396.3 53

3-methyl-4-{4- [methyl(6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5-yl)amino]phthalazin-1- yl}phenol 1.14 409.2 410.3 54

4-mesityl-N-(2- methylbenzyl)phthalazin- 1-amine 1.15 367.2 368.3 55

4-mesityl-N-[(1R)-1-(4- methoxyphenyl)ethyl] phthatazin-1-amine 1.15397.2 398.3 56

4-mesityl-N-[(1S)-1-(4- methoxyphenyl)ethyl] phthalazin-1-amine 1.14397.2 398.3 57

N-benzyl-4-mesityl-N- methylphthalazin-1-amine 1.14 367.2 368.3 58

4-mesityl-N-methyl-N-(2- methylbenzyl)phthalazin- 1-amine 1.16 381.2382.3 59

N-(2-chlorobenzyl)-4- mesityl-N- methylphthalazin-1-amine 1.16 401.2402.2 60

4-mesityl-N-(2- methoxybenzyl)-N- methylphthalazin-1-amine 1.14 397.2398.3 61

4-mesityl-N-(3- methoxybenzyl)-N- methylphthalazin-1-amine 1.15 397.2398.3 62

4-mesityl-N-(4- methoxybenzyl)-N- methylphthalazin-1-amine 1.15 397.2398.3 63

N-(3,4-dihydro-2H- chromen-4-yl)-4-mesityl- N-methylphthalazin-1- amine1.15 409.2 410.3 64

N,N-bis(1,3-benzodioxol- 5-ylmethyl)-4- mesitylphthalazin-1-amine 1.22531.2 532.3 65

4-(2-methoxy-4,6- dimethylphenyl)-N,N- dipropylphthalazin-1- amine 1.13363.2 364.3 66

N-(3,4-dihydro-2H- chromen-4-yl)-4-(2- methoxy-4,6-dimethylphenyl)phthalazin- 1-amine 1.13 411.2 412.3 67

4-(2,6-dimethylphenyl)-N- methyl-N-(1,2,3,4- tetrahydronaphthalen-1-yl)phthalazin-1-amine 1.16 393.2 394.3 68

N-(3,4-d ihydro-2H- chromen-4-yl)-4-(2,6- dimethylphenyl)-N-methylphthalazin-1-amine 1.14 395.2 396.3 69

N-(cyclopropylmethyl)-4- (2,6-dimethylphenyl)-N-propylphthalazin-1-amine 1.13 345.2 346.1 70

4-(2,6-dimethylphenyl)-N- methyl-N-[(1S)-1- phenylethyl]phthalazin-1-amine 1.13 367.2 368.1 71

4-[4- (dipropylamino)phthalazin- 1-yl]-3,5-dimethylphenol 1.08 349.2350.3 72

4-(2,6-dimethylphenyl)-N- methyl-N-[1-(2- methylphenyl)ethyl]phthalazin-1-amine 73

N-[1-(1,3-benzodioxo1-5- yl)ethyl]-4-(2,6- dimethylphenyl)-N-methylphthalazin-1-amine 74

4-(2,6-dimethylphenyl)-N- [(1R)-1-(3- methoxyphenyl)ethyl]-N-methylphthalazin-1-amine 1.14 397.2 398.3 75

N-benzyl-4-(2,6- dimethylphenyl)-N- isopropylphthalazin-1- amine 1.14381.2 382.3 76

N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)- 4-(2,6-dimethylphenyl)-N-methylphthalazin-1-amine 1.12 411.2 412.2 77

N-(2,3-dihydro-1,4- benzodioxin-6-ylmethyl)- 4-(2,6-dimethylphenyl)-N-propylphthalazin-1-amine 1.15 439.2 440.3 78

4-(2,6-dimethylphenyl)-N- (3-ethoxybenzyl)-N- methylphthalazin-1-amine1.15 397.2 398.2 79

4-(2,6-dimethylphenyl)-N- (3-ethoxybenzyl)-N- propylphthalazin-1-amine1.19 425.2 426.3 80

rel-N-[(4aR,8aS)- decahydronaphthalen-1- yl]-4-(2,6- dimethylphenyl)-N-methylphthalazin-1-amine 81

N-(1-cyclohexylethyl)-4- (2,6-dimethylphenyl)-N-methylphthalazin-1-amine 82

4-(2,6-dimethylphenyl)-N- (3-methoxybenzyl)-N- methylphthalazin-1-amine1.13 383.2 384.2 83

4-(2,6-dimethylphenyl)-N- methyl-N-[3- (trifluoromethyl)benzyl]phthalazin-1-amine 1.16 421.2 422.2 84

4-(2,6-dimethylphenyl)-N- methyl-N-[4- (trifluoromethyl)benzyl]phthalazin-1-amine 1.17 421.2 422.2 85

4-(2,6-dimethylphenyl)-N- methyl-N-[2- (trifluoromethyl)benzyl]phthalazin-1-amine 1.05 421.2 250.2 86

N-(cyclopropylmethyl)-4- (2,6-diethylphenyl)-N- propylphthalazin-1-amine1.16 373.3 374.2 87

1-(5-chloro-2- methoxyphenyl)-4-(1- propyl-3,4-dihydroisoquinolin-2(1H)- yl)phthalazine 88

1-(2-fluorophenyl)-4-(1- propyl-3,4- dihydroisoquinolin-2(1H)-yl)phthalazine 89

1-(2-methylphenyl)-4-[2- (2-phenylethyl)piperidin- 1-yl]phthalazine 90

N-methyl-N-(1- phenylethyl)-4-quinolin-8- ylphthalazin-1-amine 1.08390.2 391.3 91

1-(2-chlorophenyl)-4-(1- propyl-3,4- dihydroisoquinolin-2(1H)-yl)phthalazine 1.21 413.2 414.2 92

1-(1-propyl-3,4- dihydroisoquinolin-2(1H)- yl)-4-quinolin-8-ylphthalazine 93

1-(1-propyl-3,4- dihydroisoquinolin-2(1H)- yl)-4-[2-(trifluoromethyl)phenyl] phthalazine 1.22 447.2 448.3 94

N-butyl-N-ethyl-4- quinolin-8-ylphthalazin-1- amine 95

1-azepan-1-yl-4-(4- chlorophenyl)phthalazine 96

1-(1-ethyl-3,4- dihydroisoquinolin-2(1H)- yl)-4-mesitylphthalazine 1.19407.2 408.3 97

1-(2,4-dimethoxyphenyl)- 4-(1-ethyl-3,4- dihydroisoquinolin-2(1H)-yl)phthalazine 1.13 425.2 426.3 98

4-[4-(1-ethyl-3,4- dihydroisoquinolin-2(1H)- yl)phthalazin-1-yl]-3-methylphenol 1.14 395.2 396.1 99

1-(3,4-dihydroisoquinolin- 2(1H)-yl)-4- mesitylphthalazine 1.16 379.2380.1 100

1-mesityl-4-(1-methyl-3,4- dihydroisoquinolin-2(1H)- yl)phthalazine 1.18393.2 394.1 101

1-mesityl-4-(1-propyl-3,4- dihydroisoquinolin-2(1H)- yl)phthalazine 1.22421.3 422.2 102

1-(1-cyclopropyl-3,4- dihydroisoquinolin-2(1H)- yl)-4-mesitylphthalazine1.22 419.2 420.1 103

1-(2-ethylpiperidin-1-yl)- 4-mesitylphthalazine 1.15 359.2 360.3 104

1-(6,7-dimethoxy-1- methyl-3,4- dihydroisoquinolin-2(1H)-yl)-4-mesitylphthalazine 1.15 453.2 454.3 105

4-[4-(3,4- dihydroisoquinolin-2(1H)- yl)phthalazin-1-yl]-3- methylphenol1.09 367.2 368.2 106

3-methyl-4-[4-(1-methyl- 3,4-dihydroisoquinan- 2(1H)-yl)phthalazin-1-yl]phenol 1.12 381.2 382.3 107

3-methyl-4-[4-(1-propyl- 3,4-dihydroisoquinolin- 2(1H)-yl)phthalazin-1-yl]phenol 1.13 409.2 410.3 108

4-[4-(1-cyclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)phthalazin-1-yl]-3- methylphenol 1.14 407.2 408.3 109

4-[4-(2-ethylpiperidin-1- yl)phthalazin-1-yl]-3- methylphenol 1.08 347.2348.3 110

1-(cyclohexylmethoxy)-4- mesitylphthalazine 1.31 360.2 361.3 111

1-(cyclohexyloxy)-4- mesitylphthalazine 1.27 346.2 347.2 112

1-(1-ethylpropoxy)-4- mesitylphthalazine 1.25 334.2 335.2 113

1-mesityl-4-(1- phenylpropoxy)phthalazine 1.28 382.2 383.3 114

1-mesityl-4-(4- phenylpiperazin-1- yl)phthalazine 1.18 408.2 409.3 115

1-[(2R)-4-(3- chloropyridin-2-yl)-2- methylpiperazin-1-yl]-4-mesitylphthalazine 1.2 457.2 458.3 116

1-(1-cyclobutyl-7- methoxy-3,4- dihydroisoquinolin-2(1H)- yl)-4-(2,6-dimethylphenyl) phthalazine 117

N-(cyclopropylmethyl)-4- (1H-indol-4-yl)-N- propylphthalazin-1-amine 118

4-(1H-indazol-4-yl)-N,N- dipropylphthalazin-1- amine 1.07 345.2 346.2119

1-butoxy-4-(2,6- dimethylphenyl) phthalazine 1.24 306.2 307.1 120

1-(2,6-dimethylphenyl)-4- (1,2,3,4- tetrahydronaphthalen-1-yloxy)phthalazine 121

1-(3,4-dihydroisoquinolin- 2(1H)-yl)-4-(2,6- dimethylphenyl)phthalazine122

4-{4- [(cyclopropylmethyl)(propyl) amino]phthalazin-1-yl}-1H-indole-3-carbonitrile 1.09 381.2 382.2 123

1-(2,6-dimethylphenyl)-4- (3-phenylpyrrolidin-1- yl)phthalazine 1.11379.2 380.2 124

1-mesityl-4-(pyrrolidin-2- ylmethoxy)phthalazine 1.09 347.2 348.1 125

1-(2,6-dimethylmorpholin- 4-yl)-4-mesitylphthalazine 1.14 361.2 362.3126

1-(2,6-dimethylphenyl)-4- (1-methyl-3,4- dihydroisoquinan-2(1H)-yl)phthalazine 1.2 379.2 381.3 127

1-(1-cyclopropyl-3,4- dihydroisoquinolin-2(1H)- yl)-4-(2,6-dimethylphenyl)phthalazine 1.25 405.2 406.3 128

1-[4-(2-chloro-4- fluorophenoxy)piperidin- 1-yl]-4-(2,6-dimethylphenyl)phthalazine 1.25 461.2 462.3 129

1-(1-cyclopropyl-3,4- dihydroisoquinolin-2(1H)- yl)-4-(2,5-difluorophenyl)phthalazine 1.27 413.2 414.3 130

ethyl 4-chloro-3-[4-(1- cyclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)phthalazin-1- yl]benzoate 1.31 483.2 484.3

Example 7 Pharmaceutical Preparations of Oral and IntravenousAdministration

A. Tablets containing a C5a antagonist and an anti-arthritic agent thatis not a C5a receptor antagonist can be prepared as illustrated below:

Ingredient Amount C5a receptor antagonist 5 mg-500 mg C5areceptor-inactive therapeutic agent 1 mg-500 mg diluent, binder,disintigrant, lubricant, excipients q.s. 200-400 mg.B. Tablets containing a C5a receptor antagonist as the only activeingredient can be prepared as illustrated below:

Ingredient mg mg C5a receptor antagonist 10 50 MicrocrystallineCellulose 70.4 352 Granular Mannitol 15.1 75.5 Croscarmellose Sodium 3.015.0 Colloidal Silicon Dioxide 0.5 2.5 Magnesium Stearate (ImpalpablePowder) 1.0 5.0 Total (mg) 100 500C. Tablets containing a C5a receptor antagonist and a C5a receptorinactive agent may be prepared as follows:

Insredient mg mg C5a receptor antagonist 10 25 C5a receptor inactivetherapeutic agent 10 25 Microcrystalline Cellulose 40 100 Modified foodcorn starch 1.05 4.25 Magnesium stearate 1.25 0.5D. Intravenous formulations containing a C5a receptor antagonist and aC5a receptor inactive agent may be prepared as follows:

Ingredient Amount C5a receptor antagonist 0.5-10 mg C5a receptorinactive therapeutic agent 0.5-10 mg Sodium Citrate 5-50 mg Citric Acid1-15 mg Sodium Chloride 1-8 mg Water for Injection to 1.0 literE. Oral suspensions containing a C5a receptor antagonist and a C5areceptor inactive agent may be prepared as follows:

Insredient Amount per 5 mL dose C5a receptor antagonist 5-100 mg C5areceptor inactive therapeutic agent 5-100 mg Polyvinylpyrrolidone 150 mgPoly oxyethylene sorbitan monolaurate 25 mg Benzoic Acid 10 mg to 5 mLwith sorbitol solution (70%)

Example 8 Preparation of Radiolabeled Probes

Compounds provided herein are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably at least oneof carbon (preferably ¹⁴C), hydrogen (preferably ³H), sulfur (preferably³⁵S), or iodine (preferably ¹²⁵I). Such radiolabeled probes areconveniently synthesized by a radioisotope supplier specializing incustom synthesis of radiolabeled probe compounds. Such suppliers includeAmersham Corporation, Arlington Heights, Ill.; Cambridge IsotopeLaboratories, Inc. Andover, Mass.; SRI International, Menlo Park,Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSynLaboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St.Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using a compound providedherein as substrate. In addition, certain precursors may be subjected totritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 9 Assay for C5a Receptor Mediated Chemotaxis

This Example provides a standard assay of C5a receptor-mediatedchemotaxis.

Human promonocytic U937 cells (or purified human or non-humanneutrophils) are treated with dibutyryl cAMP for 48 h prior toperforming the assay. Human neutrophils or those from another mammalianspecies are used directly after isolation. The cells are pelleted andresuspended in culture media containing 0.1% fetal bovine serum (FBS)and 10 μg/mL calcein AM (a fluorescent dye). This suspension is thenincubated at 37° C. for 30 min such that the cells take up thefluorescent dye. The suspension is then centrifuged briefly to pelletthe cells, which are then resuspended in culture media containing 0.1%FBS at a concentration of approximately 3×10⁶ cells/mL. Aliquots of thiscell suspension are transferred to clean test tubes, which containvehicle (1% DMSO in culture media containing 0.1% FBS) or varyingconcentrations of a compound of interest, and are incubated at roomtemperature for at least 30 min. The chemotaxis assay is performed inCHEMO TX 101-8, 96 well plates (Neuro Probe, Inc.; Gaithersburg, Md.).The bottom wells of the plate are filled with medium containing 0-10 nMof C5a, preferably derived from the same species of mammal as are theneutrophils or other cells (e.g., human C5a for human U937 cells). Thetop wells of the plate are filled with cell suspensions (compound- orvehicle-treated). The plate is then placed in a tissue culture incubatorfor 60 min. The top surface of the plate is washed with PBS to removeexcess cell suspension. The number of cells that have migrated into thebottom well is then determined using a fluorescence reader. Chemotaxisindex (the ratio of migrated cells to total number of cells loaded) isthen calculated for each compound concentration to determine an EC₅₀value.

As a control to ensure that cells retain chemotactic ability in thepresence of the compound of interest, the bottom wells of the plate maybe filled with varying concentrations chemo-attractants that do notmediate chemotaxis via the C5a receptor, such as zymosan-activated serum(ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4(LTB4), rather than C5a, under which conditions compounds providedherein preferably do not detectably inhibit chemotaxis. Preferred C5areceptor modulators exhibit EC₅₀ values of less than 11 μM in the aboveassay for C5a mediated chemotaxis.

Example 10 Expression of a C5a Receptor

A human C5a receptor cDNA is obtained by PCR using 1) a forward primeradding a Kozak ribosome binding site and 2) a reverse primer that addsno additional sequence, and 3) an aliquot of a Stratagene Human FetalBrain cDNA library as template. The sequence of the resulting PCRproduct is described in PCT International Application WO 02/49993 as SEQID NO:1. The PCR product is subcloned into the cloning vector pCR-ScriptAMP (STRATAGENE, La Jolla, Calif.) at the Srf I site. It is then excisedusing the restriction enzymes EcoRI and NotI and subcloned in theappropriate orientation for expression into the baculoviral expressionvector pBacPAK 9 (CLONTECH, Palo Alto, Calif.) that has been digestedwith EcoRI and NotI.

Example 11 Baculoviral Preparations for C5a Expression

The human C5a (hC5a) receptor baculoviral expression vector isco-transfected along with BACULOGOLD DNA (BD PharMingen, San Diego,Calif.) into Sf9 cells. The Sf9 cell culture supernatant is harvestedthree days post-transfection. The recombinant virus-containingsupernatant is serially diluted in Hink's TNM-FH insect medium (JABBiosciences, Kansas City) supplemented Grace's salts and with 4.1 mML-Gln, 3.3 g/L LAB, 3.3 g/L ultrafiltered yeastolate and 10%heat-inactivated fetal bovine serum (hereinafter “insect medium”) andplaque assayed for recombinant plaques. After four days, recombinantplaques are selected and harvested into 1 mL of insect medium foramplification. Each 1 mL volume of recombinant baculovirus (at passage0) is used to infect a separate T25 flask containing 2×10⁶ Sf9 cells in5 mL of insect medium. After five days of incubation at 27° C.,supernatant medium is harvested from each of the T25 infections for useas passage 1 inoculum.

Two of seven recombinant baculoviral clones are then chosen for a secondround of amplification, using 1 mL of passage 1 stock to infect 1×10⁸cells in 100 mL of insect medium divided into 2 T175 flasks. Forty-eighth post infection, passage 2 medium from each 100 mL prep is harvestedand plaque assayed for titer. The cell pellets from the second round ofamplification are assayed by affinity binding as described below toverify recombinant receptor expression. A third round of amplificationis then initiated using a multiplicity of infection of 0.1 to infect aliter of Sf9 cells. Forty h post-infection the supernatant medium isharvested to yield passage 3 baculoviral stock.

The remaining cell pellet is assayed for affinity binding using theprotocol of DeMartino et al. (1994) J. Biol. Chem. 269(20):14446-14450(which is incorporated herein by reference for its teaching of bindingassays at page 14447), adapted as follows. Radioligand is 0.005-0.500 nM[¹²⁵I]C5a (human recombinant) (New England Nuclear Corp., Boston,Mass.); the hC5a receptor-expressing baculoviral cells are used insteadof 293 cells; the assay buffer contains 50 mM Hepes pH. 7.6, 1 mM CaCl₂,5 mM MgCl₂, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and 100 KIU/mLaprotinin; filtration is carried out using GF/C WHATMAN filters(presoaked in 1.0% polyethyeneimine for 2 h prior to use); and thefilters are washed twice with 5 mL cold binding buffer without BSA,bacitracin, or aprotinin.

Titer of the passage 3 baculoviral stock is determined by plaque assayand a multiplicity of infection, incubation time course, binding assayexperiment is carried out to determine conditions for optimal receptorexpression.

A multiplicity of infection of 0.1 and a 72-hour incubation period werethe best infection parameters found for hC5a receptor expression in upto 1-liter Sf9 cell infection cultures.

Example 12 Baculoviral Infections

Log-phase Sf9 cells (INVITROGEN Corp., Carlsbad Calif.), are infectedwith one or more stocks of recombinant baculovirus followed by culturingin insect medium at 27° C. Infections are carried out either only withvirus directing the expression of the hC5a receptor or with this virusin combination with three G-protein subunit-expression virus stocks: 1)rat G□₁₂ G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2) bovineb1 G-protein-encoding virus stock (BIOSIGNAL #V5H012), and 3) human g2G-protein-encoding virus stock (BIOSIGNAL #V6B003), which may beobtained from BIOSIGNAL Inc., Montreal.

The infections are conveniently carried out at a multiplicity ofinfection of 0.1:1.0:0.5:0.5. At 72 h post-infection, a sample of cellsuspension is analyzed for viability by trypan blue dye exclusion, andthe remaining Sf9 cells are harvested via centrifugation (3000 rpm/10min/4° C.).

Example 13 Purified Recombinant Insect Cell Membranes

Sf9 cell pellets are resuspended in homogenization buffer (10 mM HEPES,250 mM sucrose, 0.5 μg/mL leupeptin, 2 μg/mL Aprotinin, 200 μM PMSF, and2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer(setting 5 for 30 seconds). The homogenate is centrifuged (536×g/10min/4° C.) to pellet the nuclei. The supernatant containing isolatedmembranes is decanted to a clean centrifuge tube, centrifuged(48,000×g/30 min, 4° C.) and the resulting pellet resuspended in 30 mLhomogenization buffer. This centrifugation and resuspension step isrepeated twice. The final pellet is resuspended in ice cold Dulbecco'sPBS containing 5 mM EDTA and stored in frozen aliquots at −80° C. untilneeded. The protein concentration of the resulting membrane preparation(hereinafter “P2 membranes”) is conveniently measured using a Bradfordprotein assay (Bio-Rad Laboratories, Hercules, Calif.). By this measure,a 1-liter culture of cells typically yields 100-150 mg of total membraneprotein.

Example 14 Radioligand Binding Assays

Purified P2 membranes, prepared by the method given above, areresuspended by Dounce homogenization (tight pestle) in binding buffer(50 mM Hepes pH. 7.6, 120 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, 0.1% BSA, pH7.4, 0.1 mM bacitracin, 100 KIU/mL aprotinin).

For saturation binding analysis, membranes (5-50 μg) are added topolypropylene tubes containing 0.005-0.500 nM [¹²⁵I]C5a (human(recombinant), New England Nuclear Corp., Boston, Mass.) with a finalassay volume of 0.25 ml. Nonspecific binding is determined in thepresence of 300 nM hC5a (Sigma Chemical Co., St. Louis, Mo.) andaccounted for less than 10% of total binding. For evaluation of guaninenucleotide effects on receptor affinity, GTPγS is added to duplicatetubes at the final concentration of 50 μM.

For competition analysis, membranes (5-50 μg) are added to polypropylenetubes containing 0.030 nM [¹²³I]C5a (human). Non-radiolabeled displacersare added to separate assays at concentrations ranging from 10⁻¹⁰ M to10 M to yield a final volume of 0.250 mL. Nonspecific binding isdetermined in the presence of 300 nM hC5a (Sigma Chemical Co., St.Louis, Mo.) and accounted for less than 10% of total binding. Followinga 2-hour incubation at room temperature, the reaction is terminated byrapid vacuum filtration. Samples are filtered over presoaked (in 1.0%polyethyleneimine for 2 h prior to use) GF/C WHATMAN filters and rinsed2 times with 5 mL cold binding buffer without BSA, bacitracin, oraprotinin. Remaining bound radioactivity is quantified by gammacounting. K₁ and Hill coefficient (“nH”) are determined by fitting theHill equation to the measured values with the aid of SIGMAPLOT software.

Example 15 Agonist-Stimulated GTP Binding

Agonist-stimulated GTP-gamma³⁵S binding (“GTP binding”) activity can beused to identify agonist and antagonist compounds and to differentiateneutral antagonist compounds from those that possess inverse agonistactivity. This activity can also be used to detect partial agonismmediated by antagonist compounds. A compound being analyzed in thisassay is referred to herein as a “test compound.” Agonist-stimulated GTPbinding activity is measured as follows: Four independent baculoviralstocks (one directing the expression of the hC5a receptor and threedirecting the expression of each of the three subunits of aheterotrimeric G-protein) are used to infect a culture of Sf9 cells asdescribed above.

Agonist-stimulated GTP binding on purified membranes (prepared asdescribed above) is assessed using hC5a (Sigma Chemical Co., St. Louis,Mo., USA) as agonist in order to ascertain that thereceptor/G-protein-alpha-beta-gamma combination(s) yield a functionalresponse as measured by GTP binding.

P2 membranes are resuspended by Dounce homogenization (tight pestle) inGTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgCl2, 2mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100KIU/mL aprotinin, 5 μM GDP) andadded to reaction tubes at a concentration of 30 μg protein/reactiontube. After adding increasing doses of the agonist hC5a atconcentrations ranging from 10⁻¹² M to 10⁻⁶ M, reactions are initiatedby the addition of 100 μM GTPgamma³⁵S with a final assay volume of 0.25ml. In competition experiments, non-radiolabeled test compounds (e.g.,compounds of Formula I) are added to separate assays at concentrationsranging from 10⁻¹⁰ M to 10⁻⁵ M along with 10 nM hC5a to yield a finalvolume of 0.25 mL.

Neutral antagonists are those test compounds that reduce theC5a-stimulated GTP binding activity towards, but not below, baseline(the level of GTP bound by membranes in this assay in the absence ofadded C5a or other agonist and in the further absence of any testcompound).

In contrast, in the absence of added C5a, certain preferred compoundsreduce the GTP binding activity of the receptor-containing membranesbelow baseline, and are thus characterized as inverse agonists. If atest compound that displays antagonist activity does not reduce the GTPbinding activity below baseline in the absence of the C5a agonist, it ischaracterized as a neutral antagonist.

An antagonist test compound that elevates GTP binding activity abovebaseline in the absence of added hC5a in this assay is characterized ashaving partial agonist activity. Preferred antagonist compounds providedherein do not elevate GTP binding activity under such conditions morethan 10% above baseline, preferably not more than 5% above baseline, andmost preferably not more than 2% above baseline.

Following a 60-minute incubation at room temperature, the reactions areterminated by vacuum filtration over GF/C filters (pre-soaked in washbuffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mMTris pH 7.0, 120 mM NaCl). The amount of receptor-bound (and therebymembrane-bound) GTPgamma³⁵S is determined by measuring the boundradioactivity, preferably by liquid scintillation spectrometry of thewashed filters. Non-specific binding is determined using 10 mM GTPgammaSand typically represents less than 5 percent of total binding. Data isexpressed as percent above basal (baseline). The results of these GTPbinding experiments is analyzed using SIGMAPLOT software (SPSS Inc.,Chicago, Ill.).

Example 16 Calcium Mobilization Assays

A. Response to C5a

U937 cells are grown in differentiation media (1 mM dibutyrl cAMP inRPMI 1640 medium containing 10% fetal bovine serum) for 48 h at 37° C.then reseeded onto 96-well plates suitable for use in a FLIPR™ PlateReader (Molecular Devices Corp., Sunnyvale Calif.). Cells are grown anadditional 24 h (to 70-90% confluence) before the assay. The cells arethen washed once with Krebs Ringer solution. FLUO-3 calcium sensitivedye (Molecular Probes, Inc. Eugene, Oreg.) is added to 10 μg/mL andincubated with the cells in Krebs Ringer solution at room temperaturefor 1 to 2 h. The 96 well plates are then washed to remove excess dye.Fluorescence responses, measured by excitation at 480 nM and emission at530 nM, are monitored upon the addition of human C5a to the cells to afinal concentration of 0.01-30.0 nM, using the FLIPR™ device (MolecularDevices). Differentiated U937 cells typically exhibit signals of5,000-50,000 Arbitrary Fluorescent Light Units in response to agoniststimulation.

B. Assays for Determination of ATP Responses

Differentiated U937 cells (prepared and tested as described above under“A. Response to C5a”) are stimulated by the addition of ATP (rather thanC5a) to a final concentration of 0.01 to 30 μM. This stimulationtypically triggers a signal of 1,000 to 12,000 arbitrary fluorescencelight units. Certain preferred compounds produce less than a 10%,preferably less than a 5%, and most preferably less than a 2% alterationof this calcium mobilization signal when this control assay is carriedout in the presence or absence of the compounds.

C. Assays for the Identification of Receptor Modulatory Agents:Antagonists and Agonists

Those of skill in the art will recognize that the calcium mobilizationassay described above may be readily adapted for identifying testcompounds as having agonist or antagonist activity at the human C5areceptor.

For example, in order to identify antagonist compounds, differentiatedU937 cells are washed and incubated with Fluo-3 dye as described above.One h prior to measuring the fluorescence signal, a subset of the cellsis incubated with a 1 μM concentration of at least one compound to betested. The fluorescence response upon the subsequent addition of 0.3 nM(final concentration) human recombinant C5a is monitored using theFLIPR™ plate reader. Antagonist compounds elicit at least a 2-folddecrease in the fluorescence response relative to that measured in thepresence of human C5a alone. Preferred antagonist compounds elicit atleast a 5-fold, preferably at least a 10-fold, and more preferably atleast a 20-fold decrease in the fluorescence response relative to thatmeasured in the presence of human C5a alone. Agonist compounds elicit anincrease in fluorescence without the addition of C5a, which increasewill be at least partially blocked by a known C5a receptor antagonist.

If multiple concentrations of antagonist compound are examined asdescribed in the preceding paragraph, the concentration required toprovide a 50% inhibition of the 0.3 nM C5a response (hereafter referredto as IC₅₀) can be determined. The IC₅₀ value is calculated by fittingthe percent inhibition calculated from the relative fluorescence units(RFU) obtained at the FLIPR against the concentration of antagonistcompound to the following equation:

y=m ₁*(1/(1+(m ₂ /m ₀)^(m3))),

where y=% Inhibition of C5a-induced signal, m₀=antagonist compoundconcentration, m₁=maximum inhibition of C5a-induced signal by highestconcentration of antagonist compound, m₂=IC₅₀, and m₃=Hill slope. Thedata are fit to this equation using a least squares regression todetermine IC₅₀ and Hill slope. The K_(i) is calculated using theCheng-Prusoff equation:

Ki=IC ₅₀/(I+[L]/K _(d)),

where IC₅₀ is determined as described above, [L] is the C5aconcentration used to test antagonist compound activity, and K_(d) isthe dissociation constant of recombinant human C5a.

Example 17 Assays to Evaluate Agonist Activity of Small Molecule C5aReceptor Antagonists

Certain preferred compounds of Formula I are C5a receptor antagoniststhat do not possess significant (e.g., greater than 5%) agonist activityin any of the C5a mediated functional assays discussed herein. Suchagonist activity can be evaluated, for example, in the assay of C5ainduced GTP binding given above, by measuring small molecule mediatedGTP binding in the absence of the natural agonist, C5a. Similarly, in acalcium mobilization assay such as the assay described above a smallmolecule compound can be directly assayed for the ability of thecompound to stimulate calcium levels in the absence of the naturalagonist, C5a. The preferred extent of C5a agonist activity exhibited bycertain compounds provided herein is less than 10%, more preferably lessthan 5% and most preferably less than 2% of the response elicited by thenatural agonist, C5a.

Example 18 MDCK Toxicity Assay

This Example illustrates the evaluation of compound toxicity using aMadin Darby canine kidney (MDCK) cell cytotoxicity assay.

1 μL of test compound is added to each well of a clear bottom 96-wellplate (PACKARD, Meriden, Conn.) to give final concentration of compoundin the assay of 10 micromolar, 100 micromolar or 200 micromolar. Solventwithout test compound is added to control wells. MDCK cells, ATCC no.CCL-34 (American Type Culture Collection, Manassas, Va.), are maintainedin sterile conditions following the instructions in the ATCC productioninformation sheet. Confluent MDCK cells are trypsinized, harvested, anddiluted to a concentration of 0.1×10⁶ cells/ml with warm (37° C.) medium(VITACELL Minimum Essential Medium Eagle, ATCC catalog #30-2003). 100 μLof diluted cells is added to each well, except for five standard curvecontrol wells that contain 100 μL of warm medium without cells. Theplate is then incubated at 37° C. under 95% O₂, 5% CO₂ for 2 h withconstant shaking. After incubation, 50 μl, of mammalian cell lysissolution” (available as a component of the PACKARD (Meriden, Conn.)ATP-LITE-M Luminescent ATP detection kit) is added per well, the wellsare covered with PACKARD TOPSEAL stickers, and plates are shaken atapproximately 700 rpm on a suitable shaker for 2 min.

Compounds causing toxicity will decrease ATP production, relative tountreated cells. The PACKARD ATP-LITE-M Luminescent ATP detection kit,product no. 6016941, is generally used according to the manufacturer'sinstructions to measure ATP production in treated and untreated MDCKcells. PACKARD ATP LITE-M reagents are allowed to equilibrate to roomtemperature. Once equilibrated, the lyophilized substrate solution isreconstituted in 5.5 mL of substrate buffer solution (from kit).Lyophilized ATP standard solution is reconstituted in deionized water togive a 10 mM stock. For the five control wells, 10 μL of seriallydiluted PACKARD standard is added to each of the standard curve controlwells to yield a final concentration in each subsequent well of 200 nM,100 nM, 50 nM, 25 nM and 12.5 nM. PACKARD substrate solution (50 μL) isadded to all wells, which are then covered, and the plates are shaken atapproximately 700 rpm on a suitable shaker for 2 min. A white PACKARDsticker is attached to the bottom of each plate and samples are darkadapted by wrapping plates in foil and placing in the dark for 10 min.Luminescence is then measured at 22° C. using a luminescence counter(e.g., PACKARD TOPCOUNT Microplate Scintillation and LuminescenceCounter or TECAN SPECTRAFLUOR PLUS); and ATP levels calculated from thestandard curve. ATP levels in cells treated with test compound(s) arecompared to the levels determined, for untreated cells. Cells treatedwith 10 μM of a preferred test compound exhibit ATP levels that are atleast 80%, preferably at least 90%, of the untreated cells. When a 100μM concentration of the test compound is used, cells treated withpreferred test compounds exhibit ATP levels that are at least 50%,preferably at least 80%, of the ATP levels detected in untreated cells.

1. A compound according to Formula I

or a pharmaceutically acceptable salt thereof, wherein: R₂ is selectedfrom —NR₄R₅, —NR₅R₆, —(CR_(A)R_(B))OR₄, —CR_(A)R_(B)NR₄R₅,—C(R_(A′))═CR_(A)R_(B), Q, or —CR_(A)R_(B)Q; R₁ is selected fromhydrogen, halogen, cyano, amino, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted cycloalkenyl,optionally substituted haloalkyl, optionally substituted haloalkoxy,optionally substituted alkoxy, optionally substituted cycloalkoxy,optionally substituted (cycloalkyl)alkoxy, or optionally substitutedheterocycloalkyl; R₃ is selected from halogen, hydroxy, amino, cyano,optionally substituted alkyl, optionally substituted haloalkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted alkoxy,optionally substituted haloalkoxy, optionally substituted hydroxyalkyl,optionally substituted alkoxyalkyl, optionally substituted mono- anddi-alkylamino, optionally substituted aminoalkyl,-E-(CR_(C)R_(D))_(m)—Z, or -E-(CR_(C)R_(B))_(m)—XR_(A); or R₁ and R₃,taken in combination form an optionally substituted fused carbocyclicring; R₄ is: (i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl,(3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, arylC₀-C₄alkyl, orheteroarylC₀₋₄alkyl, each of which is substituted with from 0 to 4substituents independently chosen from R_(x), C₂-C₄alkanoyl, mono- anddi-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl and XR_(y); or (ii) joined to R₅ to form,with the nitrogen to which R₄ and R₅ are bound, a heterocycle havingfrom 1 to 3 rings, 5 to 7 ring members in each ring, wherein theheterocycle is substituted with from 0 to 4 substituents independentlychosen from R_(x), oxo and W—Z; R₅ is: (i) hydrogen; (ii) C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇-carbocycle)C₀-C₄alkyl, each of whichis substituted with from 0 to 3 substituents independently chosen fromhalogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino,dimethylamino, trifluoromethyl and trifluoromethoxy; or (iii) joined toR₄ or to R₆ to form an optionally substituted heterocycle; R₆ is: (i)optionally substituted (C₄-C₁₀-carbocycle)C₀-C₄alkyl, optionallysubstituted (benzoC₄-C₇carbocycle)C₀-C₄alkyl, optionally substituted(C₃-C₇heterocycle)C₀-C₄alkyl, and optionally substituted(benzoC₃-C₇heterocycle)C₀-C₄alkyl, each of which is substituted withfrom 0 to 3 substituents independently chosen from halogen, hydroxy,amino, cyano, COOH, CONH₂, SO₂NH₂, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino,dimethylamino, trifluoromethyl, trifluoromethoxy, optionally substitutedphenyl, optionally substituted phenoxy, and C₁₋₃alkylenedioxy; or (ii)joined to R₅ to form an optionally substituted heterocycle; Ar isoptionally substituted ortho-substituted phenyl, optionally substitutednaphthyl, or optionally substituted heteroaryl, wherein Ar is optionallysubstituted heteroaryl when R₂ is —NR₄R₅; R_(A), R_(A)′, and R_(B),which may be the same or different, are independently selected at eachoccurrence from: (i) hydrogen and hydroxy, and (ii) alkyl groups,cycloalkyl groups, (cycloalkyl)alkyl groups, each of which areoptionally further substituted with one or more substituent(s)independently selected from oxo, hydroxy, halogen, cyano, amino,C₁₋₆alkoxy, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)(C₁₋₆alkyl),—NHC(═O)(C₁₋₆alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆alkyl),—NHS(O)_(n)(C₁₋₆alkyl), —S(O)_(n)(C₁₋₆ alkyl), —S(O)_(n)NH(C₁₋₆alkyl),—S(O)_(n)N(C₁₋₆ alkyl)(C₁₋₆alkyl), and Z; E is a single covalent bond,oxygen, or NR_(A); X is independently selected at each occurrence fromthe group consisting of —CH₂—, —CHR_(B)—, —O—, —C(═O)—, —C(═O)O—,—S(O)_(n)—, —NH—, —NR_(B)—, —C(═O)NH—, —C(═O)NR_(B)—, —S(O)_(n)NH—,—S(O)_(n)NR_(B)—, —NHC(═O)—, —NR_(B)C(═O)—, —NHS(O)_(n)—, and—NR_(B)S(O)_(n)—; Y and Z are independently selected at each occurrencefrom 3- to 7-membered carbocyclic or heterocyclic groups which aresaturated, unsaturated, or aromatic, which are optionally substitutedwith one or more substituents independently selected from halogen, oxo,hydroxy, amino, cyano, C₁₋₄alkyl, —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)(C₁₋₄alkyl), and —S(O)_(n)(alkyl); Q is an optionallysubstituted carbocyclic or optionally substituted heterocyclic groupwhich are saturated, unsaturated or aromatic and comprises between 3 and18 ring atoms arranged in 1, 2, or 3 rings which are fused, spiro orcoupled by a bond; m is independently selected at each occurrence fromintegers ranging from 0 to 8; and n is an integer independently selectedat each occurrence from 0, 1, and
 2. 2-67. (canceled)
 68. A compound orpharmaceutically acceptable salt thereof according to claim 1, whereinR₂ is —NR₄R₅; and Ar is heteroaryl.
 69. A compound or pharmaceuticallyacceptable salt thereof according to claim 68, wherein R₁ is chosen fromhydrogen, halogen, amino, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, mono- anddi-(C₁-C₆alkyl)amino, and (C₃-C₇cycloalkyl)C₀-C₄alkyl; R₃ is selectedfrom halogen, hydroxy, amino, cyano, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl,C₁₋₆hydroxyalkyl, mono- and di-(C₁₋₆alkyl)amino, C₁₋₆aminoalkyl,C₃₋₇cycloalkyloxy; or R₁ and R₃, taken in combination form an optionallysubstituted fused carbocyclic ring.
 70. (canceled)
 71. A compound orpharmaceutically acceptable salt thereof according to claim 68, whereinAr is pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl,pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl,indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionallymono-, di-, or tri-substituted.
 72. (canceled)
 73. A compound orpharmaceutically acceptable salt thereof according to claim 68, whereinR₄ is: (i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl,(3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl,pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl,imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl,benzoisothiazolyl or tetrahydronapthyl, each of which is substitutedwith from 0 to 4 substituents independently chosen from R_(x),C₂-C₄alkanoyl, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl and XR_(y); or (ii) joined to R₅ to form,with the nitrogen to which R₄ and R₅ are bound, a heterocycle havingfrom 1 to 3 rings, 5 to 7 ring members in each ring, wherein theheterocycle is substituted with from 0 to 4 substituents independentlychosen from R_(x), oxo and W—Z; and R₅ is: (i) hydrogen; (ii)C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇-carbocycle)C₀-C₄alkyl,each of which is substituted with from 0 to 3 substituents independentlychosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy; or(iii) joined to R₄ to form an optionally substituted heterocycle.
 74. Acompound or pharmaceutically acceptable salt thereof according to claim68, wherein: R₄ is chosen from (C₃-C₇cycloalkyl)C₀-C₄alkyl,phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl,thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl,pyrazolylC₀-C₄alkyl, indolylC₀-C₄alkyl, indazolylC₀-C₄alkyl,benzocycloalkenylC₀-C₄alkyl, decahydronaphthylC₀-C₄alkyl,benzoisothiazolylC₀-C₄alkyl, tetrahydroquinolinylC₀-C₄alkyl andtetrahydronaphthylC₀-C₄alkyl, each of which is substituted with from 0to 4 groups independently chosen from R_(x), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkyl), mono- anddi-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-memberedheterocycloalkyl)C₀-C₄alkyl, C₂-C₄alkanoyl and C₂-C₄alkanoyloxy; and R₅is C₁-C₆alkyl, C₂-C₆alkenyl or (C₃-C₇-carbocycle)C₀-C₄alkyl. 75-77.(canceled)
 78. A compound or pharmaceutically acceptable salt thereofaccording to claim 1, wherein R₂ is —NR₅R₆.
 79. A compound orpharmaceutically acceptable salt thereof according to claim 78, whereinAr is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl,imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl,indolyl, indazolyl, and triazolyl, each of which is optionally mono-,di-, or tri-substituted.
 80. A compound or pharmaceutically acceptablesalt thereof according to claim 78, wherein Ar is ortho-substitutedphenyl substituted having 1 and 3 residues independently selected fromthe group consisting of optionally substituted C₁₋₆alkyl, optionallysubstituted C₂₋₆alkenyl, optionally substituted C₂₋₆alkynyl, optionallysubstituted C₁₋₆alkoxy, optionally substituted (C₁₋₆alkoxy)C₁₋₆alkyl,optionally substituted (amino)C₁₋₆alkyl, optionally substituted mono-and di-(C₁₋₆alkyl)amino.
 81. A compound or pharmaceutically acceptablesalt thereof according to claim 78, wherein R₆ is benzyl,C₄-C₁₀carbocycle, (C₄-C₁₀carbocycle)methyl, benzoC₅-C₇-carbocycle,(benzoC₅-C₇-carbocycle)methyl, benzoC₅-C₇heterocycle,(benzoC₅-C₇heterocycle)methyl, each of which is substituted with from 0to 3 substituents independently chosen from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino,trifluoromethyl, phenoxy substituted with between 0-2 R_(x) groups,C₁₋₂alkylenedioxy, and trifluoromethoxy; and R_(x) is independentlyselected at each occurrence from the group consisting of halogen,hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH₂, SO₂NH₂,C₁-C₆alkoxycarbonyl, mono- and di-(C₁₋₆alkyl)aminocarbonyl, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy,C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, and —S(O_(n))C₁-C₆alkyl.
 82. (canceled) 83.A compound or pharmaceutically acceptable salt thereof according toclaim 78, wherein R₁ is chosen from hydrogen, halogen, amino, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl,C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, and(C₃-C₇cycloalkyl)C₀-C₄alkyl; R₃ is selected from halogen, hydroxy,amino, cyano, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆hydroxyalkyl, mono- anddi-(C₁₋₆alkyl)amino, C₁₋₆aminoalkyl, C₃₋₇cycloalkyloxy; or R₁ and R₃,taken in combination form an optionally substituted fused carbocyclicring.
 84. (canceled)
 85. A compound or pharmaceutically acceptable saltthereof according to claim 83, wherein R₁ and R₃, taken in combinationform an fused benzo ring substituted with between 0-2 R_(x) groups; andR_(x) is independently selected at each occurrence from the groupconsisting of halogen, hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH₂,SO₂NH₂, C₁-C₆alkoxycarbonyl, mono- and di-(C₁₋₆alkyl)aminocarbonyl,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino,C₁-C₆alkoxy, C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂halo alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, and —S(O_(n))C₁-C₆alkyl.
 86. A compound orpharmaceutically acceptable salt thereof according to claim 78, whereinR₅ and R₆ are joined to form a saturated 4- to 7-membered heterocyclicring that is substituted with from 0 to 3 substituents independentlychosen from halogen, hydroxy, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy,trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy,—COOH, —CH₂COOH, C₁₋₂alkoxycarbonyl, and —CH₂CO₂—C₁₋₂alkyl.
 87. Acompound or pharmaceutically acceptable salt thereof according to claim80, wherein the heterocyclic ring is azepanyl, morpholinyl,homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl,piperidinyl, or homopiperidinyl.
 88. A compound or pharmaceuticallyacceptable salt thereof according to claim 78, wherein the compound hasthe formula:

wherein: Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl,pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl,pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl,furanyl, indolyl, indazolyl, and triazolyl, each of which is optionallymono-, di-, or tri-substituted; R₁ is chosen from hydrogen, halogen,amino, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₁-C₄halo alkyl, C₁-C₄halo alkoxy, mono- and di-(C₁-C₆alkyl)amino, and(C₃-C₇cycloalkyl)C₀-C₄alkyl; R₃ is selected from halogen, hydroxy,amino, cyano, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆hydroxyalkyl, mono- anddi-(C₁₋₆alkyl)amino, C₁₋₆-aminoalkyl, C₃₋₇cycloalkyloxy; or R₁ and R₃,taken in combination form an optionally substituted fused carbocyclicring. R₅ is: (i) hydrogen; (ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,(C₃-C₇-carbocycle)C₀-C₄alkyl, each of which is substituted with from 0to 3 substituents independently chosen from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino,trifluoromethyl and trifluoromethoxy; R₁₃ represents from 0 to 3substituents independently chosen from: (i) R_(x); (ii) phenyl, phenoxy,pyridyl, and pyridyloxy, each of which is substituted with from 0 to 4substituents independently chosen from halogen, hydroxy, amino, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy and mono- and di-(C₁-C₄alkyl)amino; or (iii) two R₁₃residues, taken in combination, form a fused benzene ring which issubstituted with from 0 to 4 substituents independently chosen fromhalogen, hydroxy, COOH, CONH₂, SO₂NH₂, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, and mono- and di-(C₁-C₄alkyl)amino; G is CH₂, CHR₁₃,sulfur, oxygen or NR_(E); wherein R_(E) is: (i) hydrogen; or (ii)C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenyl or a 5- or 6-memberedheteroaryl ring, each of which is substituted with from 0 to 3substituents independently chosen from R_(x); R_(x) is independentlychosen at each occurrence from halogen, hydroxy, amino, cyano, nitro,—COOH, —C(═O)NH₂, C₁-C₆alkoxycarbonyl, mono- anddi-(C₁₋₆alkyl)aminocarbonyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- anddi-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and —S(O_(n))C₁-C₆alkyl;and x is 0, 1, 2, or
 3. 89. (canceled)
 90. A compound orpharmaceutically acceptable salt thereof according to claim 78, whereinthe compound has the formula:

wherein: Ar is ortho-substituted phenyl, 1-naphthyl, 2-naphthyl,pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl,pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl,furanyl, indolyl, indazolyl, and triazolyl, each of which is optionallymono-, di-, or tri-substituted; R₁ is chosen from hydrogen, halogen,amino, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, and(C₃-C₇cycloalkyl)C₀-C₄alkyl; R₃ is selected from halogen, hydroxy,amino, cyano, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, mono- and di-(C₁₋₆alkyl)amino,C₁₋₆aminoalkyl, C₃₋₇cycloalkyloxy; or R₁ and R₃, taken in combinationform an optionally substituted fused carbocyclic ring. R₁₃ representsfrom 0 to 3 substituents independently chosen from: (i) R_(x); (ii)phenyl, phenoxy, pyridyl, and pyridyloxy, each of which is substitutedwith from 0 to 4 substituents independently chosen from halogen,hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and mono-and di-(C₁-C₄alkyl)amino; or (iii) two R₁₃ residues, taken incombination, form a fused benzene ring which is substituted with from 0to 4 substituents independently chosen from halogen, hydroxy, COOH,CONH₂, SO₂NH₂, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and mono-and di-(C₁-C₄alkyl)amino; G is CH₂, CHR₁₃, sulfur, oxygen or NR_(E);wherein R_(E) is: (i) hydrogen; or (ii) C₁-C₆alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, phenyl or a 5- or 6-membered heteroarylring, each of which is substituted with from 0 to 3 substituentsindependently chosen from R_(x); R_(x) is independently chosen at eachoccurrence from halogen, hydroxy, amino, cyano, nitro, —COOH, —C(═O)NH₂,C₁-C₆alkoxycarbonyl, mono- and di-(C₁₋₆alkyl)aminocarbonyl, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy,C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, and —S(O_(n))C₁-C₆alkyl; and x is 0, 1, 2,or
 3. 91-98. (canceled)
 99. A pharmaceutical composition comprising atleast one compound or salt thereof according to claim 1, in combinationwith a physiologically acceptable carrier or excipient.
 100. (canceled)101. A method for inhibiting signal-transducing activity of a cellularC5a receptor, comprising contacting a cell expressing C5a receptor withat least one compound or salt thereof according to claim 1, and therebyreducing signal transduction by the C5a receptor. 102-105. (canceled)106. A method for treating a patient suffering from inflammation,rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusioninjury, bronchial asthma, stroke, myocardial infarction,atherosclerosis, ischemic heart disease, fibrosis, cardiac fibrosis,ischemia-reperfusion injury, or cystic fibrosis, comprisingadministering to the patient a therapeutically effective amount of acompound or salt thereof according to claim
 1. 107-112. (canceled) 113.A packaged pharmaceutical preparation, comprising: (a) a pharmaceuticalcomposition according to claim 99 in a container; and (b) instructionsfor using the composition to treat a patient suffering frominflammation, rheumatoid arthritis, psoriasis, cardiovascular disease,reperfusion injury, bronchial asthma, stroke, myocardial infarction,atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury.114-115. (canceled)